Vitamin d derivatives

ABSTRACT

The object of the present invention is to provide a vitamin D derivative exhibiting excellent physiological activity as medicines, in particular as therapeutic agents for skin disease including psoriasis, and having decreased hypercalcemic activity.  
     The present invention provides vitamin D derivatives represented by the general Formula ( 1 ):  
                 
 
     wherein  
     in Formula ( 1 ), X is oxygen or sulfur;  
     R 1  is hydrogen or Formula ( 2 )  
                 
 
     R 2  is hydrogen or alkyl;  
     R 3  and R 4  are hydrogen or alkyl or R 3  and R 4  together form a double bond between the  16 - and  17 -positions;  
     R 5  is hydrogen or -OR 13  in which R 13  is hydrogen or a protecting group; and  
     R 6  is hydrogen or a protecting group.

TECHNICAL FIELD

[0001] The present invention relates to novel vitamin D derivatives, andmore particularly, relates to vitamin D derivatives useful as medicines(such as therapeutic agents for skin diseases including psoriasis).

BACKGROUND ART

[0002] In vivo, vitamin D₃ is led to 25-hydroxyvitamin D₃ in liver bythe hydroxylation of the 25-position and then led to 1α,25-dihydroxyvitamin D₃ or 24R, 25-dihydroxyvitamin D₃ by thehydroxylation of the 1α- or 24-position, respectively. Among thosemetabolites, for example, 1α, 25-dihydroxyvitamin D₃ and its syntheticanalogues are known to have various physiological activities such ascalcium metabolism regulatory activities, growth inhibitory anddifferentiation inducing activities for tumor cells, andimmunoregulatory activities.

[0003] Long-term and continuous administration of vitamin D₃ has tendedto have a disadvantageous effect of causing hypercalcemia. To solve thisproblem, synthesis of various vitamin D derivatives is discussed andvitamin D derivatives having a reduced hypercalcemic effect have beenproposed (e.g., JP No. 7-330714 A and JP No. 10-231284 A).

DISCLOSURE OF THE INVENTION

[0004] An object of the present invention is to provide a novel vitaminD derivative exhibiting excellent physiological activity as medicines,in particular as therapeutic agents for skin disease includingpsoriasis, and having decreased hypercalcemic activity.

[0005] To achieve the above object to provide vitamin D derivativeshaving reduced hypercalcemic activity, the inventors of the presentinvention intensively studied compounds having either oxygen or sulfurat the 22-position. As a result of such studies, the inventors of thepresent invention have found that the stated object could be achieved byproviding vitamin D derivatives of the following Formula (1) and therebycompleted the present invention.

[0006] wherein

[0007] in Formula (1), X is oxygen or sulfur;

[0008] R₁ is hydrogen or Formula (2)

[0009] wherein

[0010] in Formula (2), A is —CO—, —CR₉R₁₀— (in which R₉ and R₁₀ arehydrogen or hydroxy), —CR₁₁═CR₁₂— (in which R₁₁ and R₁₂ are hydrogen oralkyl) or —C≡C—, R₇ and R₈ are hydrogen or optionally protected hydroxy,m is a number from 0 to 4 and n is a number from 0 to 2;

[0011] R₂ is hydrogen or alkyl;

[0012] R₃ and R₄ are hydrogen or alkyl or R₃ and R₄ together form adouble bond between the 16- and 17-positions;

[0013] R₅ is hydrogen or —OR₁₃ (in which R₁₃ is hydrogen or a protectinggroup); and

[0014] R₆ is hydrogen or a protecting group.

[0015] In other words, according to the present invention, vitamin Dderivatives of Formula (1) are provided.

[0016] Preferably, X is oxygen or sulfur; R₁ is hydrogen or Formula (2)(in which A is —CO—, —CH₂—, —CH(OH)—, —CH═CH— or —C≡C—, R₇ is hydroxy,R₈ is hydrogen, m is a number from 0 to 2 and n is a number from 0 to1); R₂ is hydrogen or C₁₋₄ alkyl; R₃ and R₄ are hydrogen or R₃ and R₄together form a double bond between the 16- and 17-positions; R₅ ishydroxy; and R₆ is hydrogen in Formula (1).

[0017] Preferably, X is oxygen or sulfur; R₁ is Formula (2) (in which Ais —CO—, —CH₂—, —CH(OH)—, —CH═CH— or —C≡C—, R₇ is hydroxy, R₈ ishydrogen, m is a number from 0 to 2 and n is a number from 0 to 1); R₂is hydrogen or methyl; R₃ and R₄ together form a double bond between the16- and 17-positions; R₅ is hydroxy; and R₆ is hydrogen in Formula (1).

[0018] Preferably, X is oxygen or sulfur; R₁ is Formula (2) (in which Ais —CO—, —CH₂—, —CH═CH— or —C≡C—, R₇ is hydroxy, R₈ is hydrogen, m is anumber from 0 to 1 and n is a number from 0 to 1); R₂ is hydrogen ormethyl; R₃ and R₄ together form a double bond between the 16- and17-positions; R₅ is hydroxy; and R₆ is hydrogen in Formula (1).

[0019] Preferably, X is oxygen; R₁ is Formula (2) (in which A is —CH₂—or —C≡C—, R₇ is hydroxy, R₈ is hydrogen, m is 1 and n is a number from 0to 1); R₂ is hydrogen or methyl; R₃ and R₄ together form a double bondbetween the 16- and 17-positions; R₅ is hydroxy; and R₆ is hydrogen inFormula (1).

[0020] Preferably, X is oxygen; R₁ is Formula (2) (in which A is —C≡C—,R₇ is hydroxy, R₈ is hydrogen, m is 1 and n is 0); R₂ is hydrogen ormethy; R₃ and R₄ together form a double bond between the 16- and17-positions; R₅ is hydroxy; and R₆ is hydrogen in Formula (1).

[0021] Preferably, X is oxygen; R₁ is hydrogen or Formula (2) (in whichA is —CH₂—, R₇ is hydroxy, R₈ is hydrogen, m is a number from 1 to 2 andn is a number from 0 to 1); R₂ is hydrogen; R₃ and R₄ are hydrogen; R₅is hydroxy; and R₆ is hydrogen in Formula (1).

[0022] According to another aspect of the present invention, there isprovided a pharmaceutical composition comprising the above-mentionedvitamin D derivative.

[0023] According to another aspect of the present invention, there isprovided a therapeutic agent for skin diseases comprising theabove-mentioned vitamin D derivative as an active ingredient.Preferably, the skin disease to be treated is psoriasis.

[0024] According to yet another aspect of the present invention, thereis provided use of the above-mentioned vitamin D derivative in themanufacture of a therapeutic agent for skin disease. Preferably, thetherapeutic agent for skin disease is used for the treatment ofpsoriasis.

[0025] According to yet another aspect of the present invention, thereis provided a method of treating a skin disease using theabove-mentioned vitamin D derivative. Preferably, the skin disease to betreated is psoriasis.

[0026] The contents of the specification of Japanese Patent ApplicationNo. 2000-117791, the application on the basis of which the presentapplication claims priority are to be incorporated in their entirety byreference.

PREFERRED MODE FOR CARRYING OUT THE INVENTION

[0027] Detailed modes and methods with respect to vitamin D derivativesrepresented by Formula (1) and pharmaceutical compositions includingthereof in accordance with the present invention are described infurther detail below.

[0028] As used herein, “alkyl” means, in general, straight-chained orbrunched C₁₋₁₅ alkyl; examples thereof include methyl, ethyl, n-propyl,i-propyl, n-butyl, s-butyl, i-butyl and t-butyl, and further includepentyl, hexyl, heptyl, octyl, nonyl, decanyl, etc. The number of carbonatoms is preferably 1 to 8, more preferably 1 to 4. As the alkyl, methylor ethyl is preferred and methyl is more preferred.

[0029] Examples of a “protecting group” include acyl, substituted silyland substituted alkyl, with acyl and substituted silyl being preferred.

[0030] “Acyl” means substituted carbonyl and the substituent of carbonylmeans hydrogen, optionally substituted lower alkyl, optionallysubstituted aryl, optionally substituted lower alkyloxy, optionallysubstituted aryloxy, optionally substituted aralkyloxy and the like. Theacyl is preferably formyl, lower alkylcarbonyl, optionally substitutedphenylcarbonyl, lower alkyloxycarbonyl, optionally substitutedphenylalkyloxycarbonyl etc., more preferably, formyl, acetyl, propionyl,butyryl, pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl,t-butoxycarbonyl, benzyloxycarbonyl, etc. As used herein, lower alkyl,lower alkyloxy, lower alkylcarbonyl and lower alkyloxycarbony mean C₁₋₆alkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylcarbonyl and C₁₋₆ alkyloxycarbonyl,respectively, unless otherwise defined.

[0031] “Substituted silyl” means lower alkyl, which may have at leastone substituent, or silyl, which is substituted with optionallysubstituted aryl; preferably substituted silyl means tri-substitutedsilyl. Preferred examples of the substituted silyl includetrimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldiphenylsilyl,t-butyldimethylsilyl and the like.

[0032] In general, “aryl” means C₆₋₂₀ aryl, preferably C₆₋₁₄ aryl.

[0033] “Substituted alkyl” means alkyl substituted with at least onesubstituent; preferred examples of the substituent include optionallysubstituted alkyloxy and optionally substituted aryl, in particular,optionally substituted lower alkyloxy. Examples of the substituted alkylwhich is substituted with optionally substituted alkyloxy such asalkyloxy include methoxymethyl, 2-methoxyethoxymethyl andtetrahydropyran-2-yl. Examples of the substituent include halogen,cyano, nitro, amino, hydroxy, lower alkyl, lower alkyloxy, loweracyloxy, sulfonyl and the like.

[0034] Non-limiting examples of the vitamin D derivatives of Formula (1)of the present invention are shown in Tables 1-17 below.

[0035] R₁ is hydrogen in Table 1 and R₁ is the following Formula (2) inTables 2-17. TABLE 1 Compound No. X R2 R3 R4 R5 R6 R1 1 O H H H OH H H 2O CH₃ H H OH H H 3 O H = OH H H 4 O CH₃ = OH H H

[0036] TABLE 2 Compound (Steric No. X R2 R3 R4 R5 R6 A configuration) mn R7 R8 5 O H H H OH H CH₂ 0 0 OH H 6 O H H H OH H CH₂ 1 0 OH H 7 O H HH OH H CH₂ 2 0 OH H 8 O H H H OH H CH₂ 3 0 OH H 9 O H H H OH H CH₂ 4 0OH H 10 O H H H OH H CH₂ 0 1 OH H 11 O H H H OH H CH₂ 1 1 OH H 12 O H HH OH H CH₂ 2 1 OH H 13 O H H H OH H CH₂ 3 1 OH H 14 O H H H OH H CH₂ 4 1OH H 15 O H H H OH H CH₂ 0 2 OH H 16 O H H H OH H CH₂ 1 2 OH H 17 O H HH OH H CH₂ 2 2 OH H 18 O H H H OH H CH₂ 3 2 OH H 19 O H H H OH H CH₂ 4 2OH H 20 O H H H OH H CH(OH) R 1 0 H H 21 O H H H OH H CH(OH) S 1 0 H H22 O H H H OH H CH(OH) R 1 1 H H 23 O H H H OH H CH(OH) S 1 1 H H 24 O HH H OH H CH(OH) R 2 0 H H 25 O H H H OH H CH(OH) S 2 0 H H 26 O H H H OHH CH(OH) R 2 1 H H 27 O H H H OH H CH(OH) S 2 1 H H

[0037] TABLE 3 Compound (Steric No. X R2 R3 R4 R5 R6 A configuration) mn R7 R8 28 O H H H OH H CH(OH) R 3 0 H H 29 O H H H OH H CH(OH) S 3 0 HH 30 O H H H OH H CH(OH) R 3 1 H H 31 O H H H OH H CH(OH) S 3 1 H H 32 OH H H OH H C=O 1 0 H H 33 O H H H OH H C=O 1 0 OH H 34 O H H H OH HCH=CH E 1 0 OH H 35 O H H H OH H CH=CH Z 1 0 OH H 36 O H H H OH H CH=CHE 2 0 OH H 37 O H H H OH H CH=CH Z 2 0 OH H 38 O H H H OH H CH=CH E 3 0OH H 39 O H H H OH H CH=CH Z 3 0 OH H 40 O H H H OH H CH=CH E 1 1 OH H41 O H H H OH H CH=CH Z 1 1 OH H 42 O H H H OH H CH=CH E 2 1 OH H 43 O HH H OH H CH=CH Z 2 1 OH H 44 O H H H OH H CH=CH E 3 1 OH H 45 O H H H OHH CH=CH Z 3 1 OH H 46 O H H H OH H C≡C 1 0 OH H 47 O H H H OH H C≡C 2 0OH H 48 O H H H OH H C≡C 3 0 OH H 49 O H H H OH H C≡C 1 1 OH H 50 O H HH OH H C≡C 2 1 OH H 51 O H H H OH H C≡C 3 1 OH H

[0038] TABLE 4 Compound (Steric No. X R2 R3 R4 R5 R6 A configuration) mn R7 R8 52 O CH₃ H H OH H CH₂ 0 0 OH H 53 O CH₃ H H OH H CH₂ 1 0 OH H 54O CH₃ H H OH H CH₂ 2 0 OH H 55 O CH₃ H H OH H CH₂ 3 0 OH H 56 O CH₃ H HOH H CH₂ 4 0 OH H 57 O CH₃ H H OH H CH₂ 0 1 OH H 58 O CH₃ H H OH H CH₂ 11 OH H 59 O CH₃ H H OH H CH₂ 2 1 OH H 60 O CH₃ H H OH H CH₂ 3 1 OH H 61O CH₃ H H OH H CH₂ 4 1 OH H 62 O CH₃ H H OH H CH₂ 0 2 OH H 63 O CH₃ H HOH H CH₂ 1 2 OH H 64 O CH₃ H H OH H CH₂ 2 2 OH H 65 O CH₃ H H OH H CH₂ 32 OH H 66 O CH₃ H H OH H CH₂ 4 2 OH H 67 O CH₃ H H OH H CH(OH) R 1 0 H H68 O CH₃ H H OH H CH(OH) S 1 0 H H 69 O CH₃ H H OH H CH(OH) R 1 1 H H 70O CH₃ H H OH H CH(OH) S 1 1 H H 71 O CH₃ H H OH H CH(OH) R 2 0 H H 72 OCH₃ H H OH H CH(OH) S 2 0 H H 73 O CH₃ H H OH H CH(OH) R 2 1 H H 74 OCH₃ H H OH H CH(OH) S 2 1 H H 75 O CH₃ H H OH H CH(OH) R 3 0 H H

[0039] TABLE 5 Compound (Steric No. X R2 R3 R4 R5 R6 A configuration) mn R7 R8 76 O CH₃ H H OH H CH(OH) S 3 0 H H 77 O CH₃ H H OH H CH(OH) R 31 H H 78 O CH₃ H H OH H CH(OH) S 3 1 H H 79 O CH₃ H H OH H C=O 1 0 H H80 O CH₃ H H OH H C=O 1 0 OH H 81 O CH₃ H H OH H CH=CH E 1 0 OH H 82 OCH₃ H H OH H CH=CH Z 1 0 OH H 83 O CH₃ H H OH H CH=CH E 2 0 OH H 84 OCH₃ H H OH H CH=CH Z 2 0 OH H 85 O CH₃ H H OH H CH=CH E 3 0 OH H 86 OCH₃ H H OH H CH=CH Z 3 0 OH H 87 O CH₃ H H OH H CH=CH E 1 1 OH H 88 OCH₃ H H OH H CH=CH Z 1 1 OH H 89 O CH₃ H H OH H CH=CH E 2 1 OH H 90 OCH₃ H H OH H CH=CH Z 2 1 OH H 91 O CH₃ H H OH H CH=CH E 3 1 OH H 92 OCH₃ H H OH H CH=CH Z 3 1 OH H 93 O CH₃ H H OH H C≡C 1 0 OH H 94 O CH₃ HH OH H C≡C 2 0 OH H 95 O CH₃ H H OH H C≡C 3 0 OH H 96 O CH₃ H H OH H C≡C1 1 OH H 97 O CH₃ H H OH H C≡C 2 1 OH H 98 O CH₃ H H OH H C≡C 3 1 OH H99 S H H H OH H CH₂ 0 0 OH H

[0040] TABLE 6 Compound (Steric No. X R2 R3 R4 R5 R6 A configuration) mn R7 R8 100 S H H H OH H CH₂ 1 0 OH H 101 S H H H OH H CH₂ 2 0 OH H 102S H H H OH H CH₂ 3 0 OH H 103 S H H H OH H CH₂ 4 0 OH H 104 S H H H OH HCH₂ 0 1 OH H 105 S H H H OH H CH₂ 1 1 OH H 106 S H H H OH H CH₂ 2 1 OH H107 S H H H OH H CH₂ 3 1 OH H 108 S H H H OH H CH₂ 4 1 OH H 109 S H H HOH H CH₂ 0 2 OH H 110 S H H H OH H CH₂ 1 2 OH H 111 S H H H OH H CH₂ 2 2OH H 112 S H H H OH H CH₂ 3 2 OH H 113 S H H H OH H CH₂ 4 2 OH H 114 S HH H OH H CH(OH) R 1 0 H H 115 S H H H OH H CH(OH) S 1 0 H H 116 S H H HOH H CH(OH) R 1 1 H H 117 S H H H OH H CH(OH) S 1 1 H H 118 S H H H OH HCH(OH) R 2 0 H H 119 S H H H OH H CH(OH) S 2 0 H H 120 S H H H OH HCH(OH) R 2 1 H H 121 S H H H OH H CH(OH) S 2 1 H H 122 S H H H OH HCH(OH) R 3 0 H H 123 S H H H OH H CH(OH) S 3 0 H H

[0041] TABLE 7 Compound (Steric No. X R2 R3 R4 R5 R6 A configuration) mn R7 R8 124 S H H H OH H CH(OH) R 3 1 H H 125 S H H H OH H CH(OH) S 3 1H H 126 S H H H OH H C=O 1 0 H H 127 S H H H OH H C=O 1 0 OH H 128 S H HH OH H CH=CH E 1 0 OH H 129 S H H H OH H CH=CH Z 1 0 OH H 130 S H H H OHH CH=CH E 2 0 OH H 131 S H H H OH H CH=CH Z 2 0 OH H 132 S H H H OH HCH=CH E 3 0 OH H 133 S H H H OH H CH=CH Z 3 0 OH H 134 S H H H OH HCH=CH E 1 1 OH H 135 S H H H OH H CH=CH Z 1 1 OH H 136 S H H H OH HCH=CH E 2 1 OH H 137 S H H H OH H CH=CH Z 2 1 OH H 138 S H H H OH HCH=CH E 3 1 OH H 139 S H H H OH H CH=CH Z 3 1 OH H 140 S H H H OH H C≡C1 0 OH H 141 S H H H OH H C≡C 2 0 OH H 142 S H H H OH H C≡C 3 0 OH H 143S H H H OH H C≡C 1 1 OH H 144 S H H H OH H C≡C 2 1 OH H 145 S H H H OH HC≡C 3 1 OH H 146 S CH₃ H H OH H CH₂ 0 0 OH H 147 S CH₃ H H OH H CH₂ 1 0OH H

[0042] TABLE 8 Compound (Steric No. X R2 R3 R4 R5 R6 A configuration) mn R7 R8 148 S CH₃ H H OH H CH₂ 2 0 OH H 149 S CH₃ H H OH H CH₂ 3 0 OH H150 S CH₃ H H OH H CH₂ 4 0 OH H 151 S CH₃ H H OH H CH₂ 0 1 OH H 152 SCH₃ H H OH H CH₂ 1 1 OH H 153 S CH₃ H H OH H CH₂ 2 1 OH H 154 S CH₃ H HOH H CH₂ 3 1 OH H 155 S CH₃ H H OH H CH₂ 4 1 OH H 156 S CH₃ H H OH H CH₂0 2 OH H 157 S CH₃ H H OH H CH₂ 1 2 OH H 158 S CH₃ H H OH H CH₂ 2 2 OH H159 S CH₃ H H OH H CH₂ 3 2 OH H 160 S CH₃ H H OH H CH₂ 4 2 OH H 161 SCH₃ H H OH H CH(OH) R 1 0 H H 162 S CH₃ H H OH H CH(OH) S 1 0 H H 163 SCH₃ H H OH H CH(OH) R 1 1 H H 164 S CH₃ H H OH H CH(OH) S 1 1 H H 165 SCH₃ H H OH H CH(OH) R 2 0 H H 166 S CH₃ H H OH H CH(OH) S 2 0 H H 167 SCH₃ H H OH H CH(OH) R 2 1 H H 168 S CH₃ H H OH H CH(OH) S 2 1 H H 169 SCH₃ H H OH H CH(OH) R 3 0 H H 170 S CH₃ H H OH H CH(OH) S 3 0 H H 171 SCH₃ H H OH H CH(OH) R 3 1 H H

[0043] TABLE 9 Compound (Steric No. X R2 R3 R4 R5 R6 A configuration) mn R7 R8 172 S CH₃ H H OH H CH(OH) S 3 1 H H 173 S CH₃ H H OH H C=O 1 0 HH 174 S CH₃ H H OH H C=O 1 0 OH H 175 S CH₃ H H OH H CH=CH E 1 0 OH H176 S CH₃ H H OH H CH=CH Z 1 0 OH H 177 S CH₃ H H OH H CH=CH E 2 0 OH H178 S CH₃ H H OH H CH=CH Z 2 0 OH H 179 S CH₃ H H OH H CH=CH E 3 0 OH H180 S CH₃ H H OH H CH=CH Z 3 0 OH H 181 S CH₃ H H OH H CH=CH E 1 1 OH H182 S CH₃ H H OH H CH=CH Z 1 1 OH H 183 S CH₃ H H OH H CH=CH E 2 1 OH H184 S CH₃ H H OH H CH=CH Z 2 1 OH H 185 S CH₃ H H OH H CH=CH E 3 1 OH H186 S CH₃ H H OH H CH=CH Z 3 1 OH H 187 S CH₃ H H OH H C≡C 1 0 OH H 188S CH₃ H H OH H C≡C 2 0 OH H 189 S CH₃ H H OH H C≡C 3 0 OH H 190 S CH₃ HH OH H C≡C 1 1 OH H 191 S CH₃ H H OH H C≡C 2 1 OH H 192 S CH₃ H H OH HC≡C 3 1 OH H 193 O H = OH H CH₂ 0 0 OH H 194 O H = OH H CH₂ 1 0 OH H 195O H = OH H CH₂ 2 0 OH H

[0044] TABLE 10 Compound (Steric No. X R2 R3 R4 R5 R6 A configuration) mn R7 R8 196 O H = OH H CH₂ 3 0 OH H 197 O H = OH H CH₂ 4 0 OH H 198 O H= OH H CH₂ 0 1 OH H 199 O H = OH H CH₂ 1 1 OH H 200 O H = OH H CH₂ 2 1OH H 201 O H = OH H CH₂ 3 1 OH H 202 O H = OH H CH₂ 4 1 OH H 203 O H =OH H CH₂ 0 2 OH H 204 O H = OH H CH₂ 1 2 OH H 205 O H = OH H CH₂ 2 2 OHH 206 O H = OH H CH₂ 3 2 OH H 207 O H = OH H CH₂ 4 2 OH H 208 O H = OH HCH(OH) R 1 0 H H 209 O H = OH H CH(OH) S 1 0 H H 210 O H = OH H CH(OH) R1 1 H H 211 O H = OH H CH(OH) S 1 1 H H 212 O H = OH H CH(OH) R 2 0 H H213 O H = OH H CH(OH) S 2 0 H H 214 O H = OH H CH(OH) R 2 1 H H 215 O H= OH H CH(OH) S 2 1 H H 216 O H = OH H CH(OH) R 3 0 H H 217 O H = OH HCH(OH) S 3 0 H H 218 O H = OH H CH(OH) R 3 1 H H 219 O H = OH H CH(OH) S3 1 H H

[0045] TABLE 11 Compound (Steric No. X R2 R3 R4 R5 R6 A configuration) mn R7 R8 220 O H = OH H C=O 1 0 H H 221 O H = OH H C=O 1 0 OH H 222 O H =OH H CH=CH E 1 0 OH H 223 O H = OH H CH=CH Z 1 0 OH H 224 O H = OH HCH=CH E 2 0 OH H 225 O H = OH H CH=CH Z 2 0 OH H 225 O H = OH H CH=CH E3 0 OH H 227 O H = OH H CH=CH Z 3 0 OH H 228 O H = OH H CH=CH E 1 1 OH H229 O H = OH H CH=CH Z 1 1 OH H 230 O H = OH H CH=CH E 2 1 OH H 231 O H= OH H CH=CH Z 2 1 OH H 232 O H = OH H CH=CH E 3 1 OH H 233 O H = OH HCH=CH Z 3 1 OH H 234 O H = OH H C≡C 1 0 OH H 235 O H = OH H C≡C 2 0 OH H235 O H = OH H C≡C 3 0 OH H 237 O H = OH H C≡C 1 1 OH H 238 O H = OH HC≡C 2 1 OH H 239 O H = OH H C≡C 3 1 OH H 240 O CH₃ = OH H CH₂ 0 0 OH H241 O CH₃ = OH H CH₂ 1 0 OH H 242 O CH₃ = OH H CH₂ 2 0 OH H 243 O CH₃ =OH H CH₂ 3 0 OH H

[0046] TABLE 12 Compound (Steric No. X R2 R3 R4 R5 R6 A configuration) mn R7 R8 244 O CH₃ = OH H CH₂ 4 0 OH H 245 O CH₃ = OH H CH₂ 0 1 OH H 246O CH₃ = OH H CH₂ 1 1 OH H 247 O CH₃ = OH H CH₂ 2 1 OH H 246 O CH₃ = OH HCH₂ 3 1 OH H 249 O CH₃ = OH H CH₂ 4 1 OH H 250 O CH₃ = OH H CH₂ 0 2 OH H251 O CH₃ = OH H CH₂ 1 2 OH H 252 O CH₃ = OH H CH₂ 2 2 OH H 253 O CH₃ =OH H CH₂ 3 2 OH H 254 O CH₃ = OH H CH₂ 4 2 OH H 255 O CH₃ = OH H CH(OH)R 1 0 H H 256 O CH₃ = OH H CH(OH) S 1 0 H H 257 O CH₃ = OH H CH(OH) R 11 H H 258 O CH₃ = OH H CH(OH) S 1 1 H H 259 O CH₃ = OH H CH(OH) R 2 0 HH 260 O CH₃ = OH H CH(OH) S 2 0 H H 261 O CH₃ = OH H CH(OH) R 2 1 H H262 O CH₃ = OH H CH(OH) S 2 1 H H 263 O CH₃ = OH H CH(OH) R 3 0 H H 264O CH₃ = OH H CH(OH) S 3 0 H H 265 O CH₃ = OH H CH(OH) R 3 1 H H 266 OCH₃ = OH H CH(OH) S 3 1 H H 267 O CH₃ = OH H C=O 1 0 H H

[0047] TABLE 13 Compound (Steric No. X R2 R3 R4 R5 R6 A configuration) mn R7 R8 268 O CH₃ = OH H C=O 1 0 OH H 269 O CH₃ = OH H CH=CH E 1 0 OH H270 O CH₃ = OH H CH=CH Z 1 0 OH H 271 O CH₃ = OH H CH=CH E 2 0 OH H 272O CH₃ = OH H CH=CH Z 2 0 OH H 273 O CH₃ = OH H CH=CH E 3 0 OH H 274 OCH₃ = OH H CH=CH Z 3 0 OH H 275 O CH₃ = OH H CH=CH E 1 1 OH H 276 O CH₃= OH H CH=CH Z 1 1 OH H 277 O CH₃ = OH H CH=CH E 2 1 OH H 278 O CH₃ = OHH CH=CH Z 2 1 OH H 279 O CH₃ = OH H CH=CH E 3 1 OH H 280 O CH₃ = OH HCH=CH Z 3 1 OH H 281 O CH₃ = OH H C≡C 1 0 OH H 282 O CH₃ = OH H C≡C 2 0OH H 283 O CH₃ = OH H C≡C 3 0 OH H 284 O CH₃ = OH H C≡C 1 1 OH H 285 OCH₃ = OH H C≡C 2 1 OH H 286 O CH₃ = OH H C≡C 3 1 OH H 287 S H = OH H CH₂0 0 OH H 288 S H = OH H CH₂ 1 0 OH H 289 S H = OH H CH₂ 2 0 OH H 290 S H= OH H CH₂ 3 0 OH H 291 S H = OH H CH₂ 4 0 OH H

[0048] TABLE 14 Compound (Steric No. X R2 R3 R4 R5 R6 A configuration) mn R7 R8 292 S H = OH H CH₂ 0 1 OH H 293 S H = OH H CH₂ 1 1 OH H 294 S H= OH H CH₂ 2 1 OH H 295 S H = OH H CH₂ 3 1 OH H 296 S H = OH H CH₂ 4 1OH H 297 S H = OH H CH₂ 0 2 OH H 298 S H = OH H CH₂ 1 2 OH H 299 S H =OH H CH₂ 2 2 OH H 300 S H = OH H CH₂ 3 2 OH H 301 S H = OH H CH₂ 4 2 OHH 302 S H = OH H CH(OH) R 1 0 H H 303 S H = OH H CH(OH) S 1 0 H H 304 SH = OH H CH(OH) R 1 1 H H 305 S H = OH H CH(OH) S 1 1 H H 306 S H = OH HCH(OH) R 2 0 H H 307 S H = OH H CH(OH) S 2 0 H H 308 S H = OH H CH(OH) R2 1 H H 309 S H = OH H CH(OH) S 2 1 H H 310 S H = OH H CH(OH) R 3 0 H H311 S H = OH H CH(OH) S 3 0 H H 312 S H = OH H CH(OH) R 3 1 H H 313 S H= OH H CH(OH) S 3 1 H H 314 S H = OH H C=O 1 0 H H 315 S H = OH H C=O 10 OH H

[0049] TABLE 15 Compound (Steric No. X R2 R3 R4 R5 R6 A configuration) mn R7 R8 316 S H = OH H CH=CH E 1 0 OH H 317 S H = OH H CH=CH Z 1 0 OH H318 S H = OH H CH=CH E 2 0 OH H 319 S H = OH H CH=CH Z 2 0 OH H 320 S H= OH H CH=CH E 3 0 OH H 321 S H = OH H CH=CH Z 3 0 OH H 322 S H = OH HCH=CH E 1 1 OH H 323 S H = OH H CH=CH Z 1 1 OH H 324 S H = OH H CH=CH E2 1 OH H 325 S H = OH H CH=CH Z 2 1 OH H 326 S H = OH H CH=CH E 3 1 OH H327 S H = OH H CH=CH Z 3 1 OH H 328 S H = OH H C≡C 1 0 OH H 329 S H = OHH C≡C 2 0 OH H 330 S H = OH H C≡C 3 0 OH H 331 S H = OH H C≡C 1 1 OH H332 S H = OH H C≡C 2 1 OH H 333 S H = OH H C≡C 3 1 OH H 334 S CH₃ = OH HCH₂ 0 0 OH H 335 S CH₃ = OH H CH₂ 1 0 OH H 336 S CH₃ = OH H CH₂ 2 0 OH H337 S CH₃ = OH H CH₂ 3 0 OH H 338 S CH₃ = OH H CH₂ 4 0 OH H 339 S CH₃ =OH H CH₂ 0 1 OH H

[0050] TABLE 16 Compound (Steric No. X R2 R3 R4 R5 R6 A configuration) mn R7 R8 340 S CH₃ = OH H CH₂ 1 1 OH H 341 S CH₃ = OH H CH₂ 2 1 OH H 342S CH₃ = OH H CH₂ 3 1 OH H 343 S CH₃ = OH H CH₂ 4 1 OH H 344 S CH₃ = OH HCH₂ 0 2 OH H 345 S CH₃ = OH H CH₂ 1 2 OH H 346 S CH₃ = OH H CH₂ 2 2 OH H347 S CH₃ = OH H CH₂ 3 2 OH H 348 S CH₃ = OH H CH₂ 4 2 OH H 349 S CH₃ =OH H CH(OH) R 1 0 H H 350 S CH₃ = OH H CH(OH) S 1 0 H H 351 S CH₃ = OH HCH(OH) R 1 1 H H 352 S CH₃ = OH H CH(OH) S 1 1 H H 353 S CH₃ = OH HCH(OH) R 2 0 H H 354 S CH₃ = OH H CH(OH) S 2 0 H H 355 S CH₃ = OH HCH(OH) R 2 1 H H 356 S CH₃ = OH H CH(OH) S 2 1 H H 357 S CH₃ = OH HCH(OH) R 3 0 H H 358 S CH₃ = OH H CH(OH) S 3 0 H H 359 S CH₃ = OH HCH(OH) R 3 1 H H 360 S CH₃ = OH H CH(OH) S 3 1 H H 361 S CH₃ = OH H C=O1 0 H H 362 S CH₃ = OH H C=O 1 0 OH H 363 S CH₃ = OH H CH=CH E 1 0 OH H

[0051] TABLE 17 Compound (Steric No. X R2 R3 R4 R5 R6 A configuration) mn R7 R8 364 S CH₃ = OH H CH=CH Z 1 0 OH H 365 S CH₃ = OH H CH=CH E 2 0OH H 366 S CH₃ = OH H CH=CH Z 2 0 OH H 367 S CH₃ = OH H CH=CH E 3 0 OH H368 S CH₃ = OH H CH=CH Z 3 0 OH H 369 S CH₃ = OH H CH=CH E 1 1 OH H 370S CH₃ = OH H CH=CH Z 1 1 OH H 371 S CH₃ = OH H CH=CH E 2 1 OH H 372 SCH₃ = OH H CH=CH Z 2 1 OH H 373 S CH₃ = OH H CH=CH E 3 1 OH H 374 S CH₃= OH H CH=CH Z 3 1 OH H 375 S CH₃ = OH H C≡C 1 0 OH H 376 S CH₃ = OH HC≡C 2 0 OH H 377 S CH₃ = OH H C≡C 3 0 OH H 378 S CH₃ = OH H C≡C 1 1 OH H379 S CH₃ = OH H C≡C 2 1 OH H 380 S CH₃ = OH H C≡C 3 1 OH H

[0052] Although the vitamin D derivatives of Formula (1) of the presentinvention can be produced according to the following process, they canbe synthesized by other processes known in the art and are therefore notlimited to the following process.

[0053] I. Synthesis of vitamin D derivatives in which R₃ and R₄ togetherform a double bond in Formula (1) I-1. Synthesis of vitamin Dderivatives in which X is oxygen in Formula (1)

[0054] Vitamin D derivatives in which X is oxygen, R₂ is hydrogen ormethyl and R₃ and R₄ together form a double bond between the 16- and17-positions in Formula (1) can be produced, for example, by the methodshown in the following scheme using a compound of Formula (A) (describedby E. Murayama, et al, Chem. Pharm. Bull., 34(10), 1986, JP No.61-267550 A, etc.) as a starting material.

[0055] wherein

[0056] TBS is a t-butyldimethylsilyl group and each R is optionallysubstituted aryl or optionally substituted alkyl.

[0057] (Step 1) Formation of hydrazone

[0058] In an appropriate solvent, Compound (A) is reacted with anarylsulfonyl or alkylsulfonyl hydrazide to synthesize Compound (B).

[0059] Examples of the arylsulfonyl or alkylsulfonyl hydrazide used forthis reaction include benzenesulfonyl hydrazide, p-toluenesulfonylhydrazide, m-toluenesulfonyl hydrazide, o-toluenesulfonyl hydrazide,4-ethylbenzenesulfonyl hydrazide, 2-mesitylenesulfonyl hydrazide,4-chlorobenzenesulfonyl hydrazide, 4-isopropylbenzenesulfonyl hydrazide,2,4,6-triisopropylbenzenesulfonyl hydrazide, methanesulfonyl hydrazide,2-methyl-2-propanesulfonyl hydrazide, 2-propanesulfonyl hydrazide,ethanesulfonyl hydrazide and the like, preferably benzenesulfonylhydrazide, p-toluenesulfonyl hydrazide and2,4,6-triisopropylbenzenesulfonyl hydrazide, and more preferably2,4,6-triisopropylbenzenesulfonyl hydrazide.

[0060] Hydrocarbon-, ether-, halogen-, ester-, amide-, alcohol-,sulfoxide- and nitrile-based solvents can be used as the solvent used inthis reaction. Examples of the solvent includes hexane, benzene,toluene, diethyl ether, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, t-butylmethyl ether, diisopropyl ether,dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, ethylacetate, methyl acetate, propyl acetate, N,N-dimethylformamide,N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, methanol, ethanol,isopropanol, dimethylsulfoxide, acetonitrile, propionitrile and thelike. Among them, toluene, diethyl ether, tetrahydrofuran,dichloromethane and ethyl acetate are preferred and tetrahydrofuran andethyl acetate are more preferred.

[0061] The reaction temperature is not particularly limited unless thereaction can proceed; the reaction is preferably carried out in therange of 0 to 100° C. and more preferably at room temperature.

[0062] (Step 2) Alkylation

[0063] Compound (B) is reacted with a base in an appropriate solvent andthen reacted with formaldehyde (or its equivalent such as1,3,5-trioxane, paraformaldehyde, etc.) or acetone to synthesizeCompound (C).

[0064] Examples of the base used in the above reaction includen-butyllithium, s-butyllithium, t-butyllithium, methyllithium,phenyllithium, methylmagnesium bromide, methylmagnesium chloride,methylmagnesium iodide, isopropylmagnesium bromide,diisopropylmagnesium, lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, lithium 2,2,6,6-tetramethylpiperidide, lithiumamide, sodium hydride, sodium bis(trimethylsilyl)amide, potassiumhydride, potassium bis(trimethylsilyl)amide and the like. Among them,n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylamideare preferred and n-butyllithium and s-butyllithium are more preferred.

[0065] In the above reaction, an appropriate metallic salt may be addedafter using the base. Examples of the metallic salt include ceriumchloride, magnesium bromide, magnesium chloride, zinc chloride, titaniumtetrachloride, chlorotitanium triisopropoxide, samarium chloride, indiumchloride and the like, with cerium chloride being preferred.

[0066] Hydrocarbon- and ether-based solvents can be used as the solventin the above reaction. Examples thereof include pentane, hexane,benzene, toluene, diethyl ether, t-butylmethyl ether, tetrahydrofuran,1,2-dimethoxyethane, 1,4-dioxane, anisole and the like. Among them,hexane, diethyl ether and tetrahydrofuran are preferred and hexane andtetrahydrofuran are more preferred.

[0067] The above reaction may be carried out in the presence of an amideor amine compound. Examples of the amide or amine compound include1,4-diazabicyclo[2,2,2]octane, N,N,N′,N′-tetramethylethylenediamine,1,3-dimethyl-2-imidazolidinone,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphotriamideand the like. Among them, N,N,N′,N′-tetramethylethylenediamine,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone andhexamethylphosphotriamide are preferred andN,N,N′,N′-tetramethylethylenediamine is more preferred.

[0068] Although the reaction temperature of using the base is notparticularly limited unless the reaction can proceed, the reaction ispreferably carried out in the range of −100° C. to 50° C. and morepreferably in the range of −80° C. to 20° C.

[0069] In the above reaction, the reaction temperature usingformaldehyde (or its equivalent such as 1,3,5-trioxane,paraformaldehyde, etc.) or acetone is not particularly limited unlessthe reaction can proceed; the reaction is preferably carried out in therange of −100° C. to 50° C. and more preferably in the range of −80° C.to 20° C.

[0070] Those compounds in which R₂ is hydrogen may also be synthesizedby the following method.

[0071] (Step 1′) Epoxidation

[0072] In an appropriate solvent, Compound (A) is reacted with atrimethylsulfonium or trimethylsulfoxonium salt in the presence of abase to give Compound (D).

[0073] Examples of the trimethylsulfonium or trimethylsulfoxonium saltused in this reaction include trimethylsulfonium iodide,trimethylsulfonium bromide, trimethylsulfonium chloride,trimethylsulfonium methylsulfate, trimethylsulfonium tetrafluoroborate,trimethylsulfonium perchlorate, trimethylsulfoxonium iodide,trimethylsulfoxonium bromide, trimethylsulfoxonium chloride,trimethylsulfoxonium methylsulfate, trimethylsulfoxoniumtetrafluoroborate, trimethylsulfoxonium perchlorate and the like, withtrimethylsulfonium bromide and trimethylsulfoxonium iodide beingpreferred.

[0074] Examples of the base used in this reaction includen-butyllithium, s-butyllithium, t-butyllithium, methyllithium,phenyllithium, methylmagnesium bromide, methylmagnesium chloride,methylmagnesium iodide, isopropylmagnesium bromide, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide, lithium2,2,6,6-tetramethylpiperidide, lithium amide, sodium hydride, sodiumbis(trimethylsilyl)amide, potassium hydride, potassiumbis(trimethylsilyl)amide, sodium hydroxide, potassium hydroxide and thelike. Among them, sodium hydride, potassium hydride, n-butyllithium,s-butyllithium, t-butyllithium, sodium hydroxide and potassium hydroxideare preferred and sodium hydride and potassium hydride are morepreferred.

[0075] Hydrocarbon-, ether-, amide- and sulfoxide-based solvents can beused as the solvent in this reaction; examples thereof include pentane,hexane, benzene, toluene, diethyl ether, t-butylmethyl ether,tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, anisol, diglyme,N,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, dimethylsulfoxideand the like, with dimethylsulfoxide being preferred. An ether-basedsolvent such as tetrahydrofuran can be added to the solvent, if desired.

[0076] The temperature of the above reaction is not particularly limitedunless the reaction can proceed; the reaction is preferably carried outin the range of −20° C. to 20° C.

[0077] (Step 2′) Ring opening of the epoxide

[0078] In an appropriate solvent, Compound (D) was reacted with an acidto synthesize Compound (C).

[0079] Examples of the acid used in this reaction include hydrochloricacid, sulfuric acid, acetic acid, phosphoric acid, aluminumtrimethoxide, aluminum triethoxide, aluminum triisopropoxide, aluminumtri-t-butoxide, aluminum chloride, zinc chloride, tin(II) chloride,tin(IV) chloride, titanium tetrachloride, titanium tetramethoxide,titanium tetraethoxide, titanium tetraisopropoxide and the like. Amongthem, aluminum trimethoxide, aluminum triethoxide, aluminumtriisopropoxide and aluminum tri-t-butoxide are preferred and aluminumtriisopropoxide is more preferred.

[0080] Hydrocarbon-, ether-, halogen- and amide-based solvents can beused in this reaction; examples thereof include pentane, hexane,benzene, 1,2-dichlorobenzene, toluene, diethyl ether, tetrahydrofuran,1,4-dioxane, t-butylmethyl ether, diglyme, 1,2-dimethoxyethane,1,4-dioxane, anisole, dichloromethane, chloroform, carbon tetrachloride,1,2-dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, dimethylsulfoxideand the like. Among them, benzene, 1,2-dichlorobenzene and toluene arepreferred and 1,2-dichlorobenzene is more preferred.

[0081] The temperature of the above reaction is not particularly limitedunless the reaction can proceed; the reaction is preferably carried outin the range of 0° C. to 200° C. and more preferably in the range of 80to 180° C.

[0082] The above reaction may be carried out by using a base instead ofan acid. Examples of the base include n-butyllithium, s-butyllithium,t-butyllithium, methyllithium, phenyllithium, methylmagnesium bromide,methylmagnesium chloride, methylmagnesium iodide, isopropylmagnesiumbromide, lithium diethylamide, lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, lithium 2,2,6,6-tetramethylpiperidide, lithiumamide, sodium hydride, sodium bis(trimethylsilyl)amide, potassiumhydride, potassium bis(trimethylsilyl)amide, diethylaluminumdiisopropylamide, diethylaluminum 2,2,6,6-tetramethylpiperidide, sodiumhydroxide, potassium hydroxide and the like. Among them, lithiumdiethylamide, diisopropyl magnesium, lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, lithium 2,2,6,6-tetramethylpiperidide, lithiumamide, sodium hydride, sodium bis(trimethylsilyl)amide, potassiumhydride, potassium bis(trimethylsilyl)amide, diethylaluminumdiisopropylamide, diethylaluminum 2,2,6,6-tetramethylpiperidide and thelike are preferred and diethylamide is more preferred.

[0083] When a base is used, hydrocarbon-, ether-, halogen- andamide-based solvents can be used. Examples thereof include pentane,hexane, benzene, 1,2-dichlorobenzene, toluene, diethyl ether,tetrahydrofuran, 1,4-dioxane, t-butylmethyl ether, diglyme,1,2-dimethoxyethane, 1,4-dioxane, anisole, dichloromethane, chloroform,carbon tetrachloride, 1,2-dichloromethane, N,N-dimethylformamide,N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, dimethylsulfoxideand the like, with benzene, toluene, diethyl ether and tetrahydrofuranbeing preferred.

[0084] The reaction temperature when the base is used is notparticularly limited unless the reaction can proceed; the reaction ispreferably carried out in the range of −40° C. to 200° C. and morepreferably in the range of 0 to 100° C.

[0085] (Step 3) Side chain introduction

[0086] For the introduction of a side chain, Compound (C) obtained fromthe above Steps (1) and (2), Steps (1′) and (2′), etc. is reacted withan alkylation agent corresponding to the side chain in the presence of abase to give Compound (E).

[0087] An alkylation agent corresponding to the side chain R₁ of thevitamin D derivative of Formula (1) of the present invention isemployed. That is, an alkylation agent of the following formula:

R_(1a)-Z

[0088] (wherein Z is a leaving group such as halogen, mesyloxy, tosyloxyand trifluoromethanesulfonyloxy and R_(1a) is a monovalent residualgroup of R₁) corresponding to R₁ of Formula (1).

[0089] Examples of R_(1a)-Z include1-bromo-4-methyl-4-(triethylsilyloxy)pentane,1-bromo-4-ethyl-4-(triethylsilyloxy)hexane,1-bromo-5-triethylsilyloxy-5-methylhexane,1-bromo-4-triethylsilyloxy-4-methyl-2-pentyne and the like.

[0090] Examples of the base include alkaline metal hydrides, alkalinemetal alkoxides, metal dialkylamides, alkaline metals and the like;sodium hydride, potassium hydride, potassium t-butoxide, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide, methyllithium,n-butyllithium and ethylmagnesium bromide are preferred, and sodiumhydride and potassium hydride are more preferred.

[0091] This reaction may be carried out in the presence of a crownether. Examples of the crown ether include 15-crown-5, 18-crown-6,dibenzo-18-crown-6 and the like.

[0092] Hydrocarbon-, ether- and amide-based solvents and the like can beused as the solvent; specific examples thereof include benzene, toluene,diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane,N,N-dimethylacetamide, N,N-dimethylformamide,1,3-dimethyl-2-imidazolidinone,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and the like. Amongthem, tetrahydrofuran, 1,2-dimethoxyethane, N,N-dimethylformamide and1,3-dimethyl-2-imidazolidinone are preferred and tetrahydrofuran is morepreferred.

[0093] The reaction temperature depends on the substance; in general,the reaction is carried out in the range of −40° C. to the boiling ordecomposition temperature of the solvent used in the reaction,preferably in the range of from 0 to 200° C. and more preferably fromabout room temperature to 120° C.

[0094] The side chain introduction is not limited to the above methodand, for example, an epoxide such as isobutyleneoxide or1,2-epoxy-2-ethylbutane may be used instead of an alkylhalide. Reactionusing an epoxide can be carried out under similar conditions to thoseusing an alkylhalide (JP No. 6-80626 A).

[0095] Furthermore, the side chain introduction may be carried out asfollows: for example, ring opening of the epoxide is carried out using areducing agent (e.g., lithium aluminum hydride, lithium borohydride,lithium tri-s-butylborohydride and lithium triethylborohydride) afteralkylation using 1-bromo-2,3-epoxy-3-methylbutane as the alkylhalide inthe presence of the above base. This reaction may be carried out by onestep or two steps (the methods of WO 98/09935).

[0096] Moreover, the side chain introduction may be carried out byalkylation using an acrylic acid derivative such as ethyl acrylate orN,N-dimethylacrylamide or a haloacetate derivative such as t-butylbromoacetate in the presence of the above base, followed by reactionwith an alkaline metal reagent such as alkyllithium reagent or Grignardreagent (method of U.S. Pat. No. 5,436,401).

[0097] (Step 4) Deprotection

[0098] According to a conventional method, protecting groups are removedfrom Compound (E) to give Compound (F).

[0099] Hydrochloric acid, sulfuric acid, acetic acid, an acidic ionexchange resin, tetrabutylammonium fluoride, hydrogen fluoride/pyridine,hydrogen fluoride/triethylamine and hydrofluoric acid can be used as thereagent, with tetrabutylammonium fluoride being preferred.

[0100] Generally, an ether-based solvent is used as the solvent andpreferably tetrahydrofuran is used. The reaction temperature depends onthe substance; in general, the reaction is preferably carried out in therange of from room temperature to 65° C.

[0101] (Step 5) Photoreaction and thermal isomerization According to aconventional method, Compound (F) is subjected to photoreaction andthermal isomerization to give Compound (G).

[0102] The order of Steps 3, 4 and 5 is not particularly limited to theabove and Steps 3, 4 and 5 may be carried out in the order of [Step3→Step 5→Step 4] or [Step 5→Step 3→Step 4]. However Step 4 is notcarried out before Step 3.

[0103] If necessary, the side chain may be modified by a known methodsuch as catalytic hydrogenation in each of the above Steps.

[0104] I-2. Synthesis of vitamin D derivatives in which X is sulfur inFormula (1)

[0105] Vitamin D derivatives in which X is sulfur, R₂ is hydrogen and R₃and R₄ together form a double bond between the 16- and 17-positions inFormula (1) can be produced, for example, by the method shown in thefollowing scheme.

[0106] (Step 3′) Introduction of sulfur functional group

[0107] Compound (H) is subjected to the following two reactions to giveCompound (I). Compound (H) corresponds to Compound (C), in which R₂ ishydrogen and which is obtainable by the above Steps (1) and (2) or Steps(1′) and (2′).

[0108] wherein Z is a leaving group, such as chloro, bromo, lodo,mesyloxy or tosyloxy.

[0109] Conversion of the leaving group of Compound (H) for obtainingCompound (M) can be carried out according to a conventional method(Larock, R. C. Comprehensive Organic Transformations, 2nd ed.,;Wiley-VCH: New York, 1999).

[0110] Compound (I) was synthesized by reacting Compound (M) with ametallic salt of thiocarboxylic or dithiocarboxylic acid in anappropriate solvent.

[0111] Examples of the metallic salt of thiocarboxylic ordithiocarboxylic acid include sodium thioacetate, potassium thioacetate,sodium thiobenzoate, potassium thiobenzoate, sodium dithioacetate,potassium dithioacetate, sodium dithiobenzoate, potassium dithiobenzoateand the like, with potassium thioacetate being preferred.

[0112] Hydrocarbon-, ether-, halogen-, ketone-, ester-, amide-,sulfoxide- and nitrile-based solvents can be used as the solvent.Examples thereof include hexane, benzene, toluene, diethyl ether,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane,chloroform, carbon tetrachloride, acetone, ethyl acetate,N,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, dimethylsulfoxide,acetonitrile and the like. Among them, diethyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, acetone, N,N-dimethylformamide,N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxideand the like are preferred, and tetrahydrofuran, acetone anddimethylsulfoxide are more preferred. Mixtures of those solvents mayalso be used in the reaction.

[0113] The reaction temperature is not particularly limited unless thereaction can proceed; in general, the reaction is carried out in therange of from −50° C. to 100° C. and preferably from 0° C. to roomtemperature.

[0114] The above two reactions may be carried out continuously. In otherwords, after converting the hydroxy to a leaving group, the resultingcompound may be reacted with a metallic salt of thiocarboxylic ordithiocarboxylic acid without work-up.

[0115] (Step 4′) Alkaline solvolysis and S-alkylation

[0116] To obtain Compound (J), Compound (I) was subjected to alkalinesolvolysis simultaneously with S-alkylation.

[0117] Lithium hydroxide, sodium hydroxide, potassium hydroxide, sodiummethoxide and potassium t-butoxide can be used for alkaline solvolysisand S-alkylation. Preferably, sodium hydroxide, potassium hydroxide orsodium methoxide is used.

[0118] Preferably, water or an alcohol-based solvent (e.g., methanol,ethanol, propanol, butanol, etc.) alone, or an ether-based solvent isused as the solvent. For example, the reaction may be carried out in asolvent system mixed with diethyl ether, tetrahydrofuran,1,2-dimethoxyethane, 1,4-dioxane, diglyme and the like.

[0119] A compound of formula R_(1a-Z) (in which Z is a leaving groupsuch as halogen, mesyloxy, tosyloxy or trifluoromethanesulfonyloxy, andR_(1a) is as defined above) or an epoxide such as isobutyleneoxide,1,2-epoxy-2-ethylbutane or 1,2-epoxy-3-methylbutane can be used as thealkylation agent.

[0120] Examples of the compound of Ria-Z include4-bromo-2-methyl-2-butanol, 1-bromo-4-methyl-4-triethylsilyl pentane,1-bromo-4-hydroxy-4-methyl-2-pentene,1-bromo-4-hydroxy-4-methyl-2-pentyne and the like.

[0121] The reaction temperature is generally in the range of from −40°C. to 100° C., preferably from 0 to 50° C. and more preferably at roomtemperature.

[0122] (Step 5′) Deprotection

[0123] According to a conventional method, protecting groups are removedfrom Compound (J).

[0124] Hydrochloric acid, sulfuric acid, acetic acid, an acidic ionexchange resin, tetrabutylammonium fluoride, hydrogen fluoride/pyridine,hydrogen fluoride/triethylamine and hydrofluoric acid can be used as thereagent, with acidic ion exchange resin and tetrabutylammonium fluoridebeing preferred.

[0125] Generally, an ether-based solvent is used as the solvent andpreferably tetrahydrofuran is used.

[0126] The reaction temperature depends on the substance; in general,the reaction is preferably carried out in the range of from roomtemperature to 65° C.

[0127] (Step 6) Photoreaction and thermal isomerization

[0128] According to a conventional method, Compound (K) is subjected tophotoreaction and thermal isomerization to give Compound (L).

[0129] The order of Steps 3′, 4′, 5′ and 6 is not particularly limitedto that order, however Steps 4′ and 5′ are not carried out before Step3′.

[0130] II-1. Synthesis of vitamin D derivatives in which R₃ and R₄ arehydrogen in Formula (1)

[0131] Vitamin D derivatives in which R₃ and R₄ are hydrogen in Formula(1) can be produced, for example, by the method shown in the followingscheme by using a compound of Formula (A′) (described in E. Murayama, etal, Chem. Pharm. Bull., 34(10), 1986, and JP No. 61-267550 A) as thestarting material.

[0132] wherein TBS is a t-butyldimethylsilyl group and each R isoptionally substituted aryl or optionally substituted alkyl. (Step 1)Methylene formation

[0133] Process for preparing a compound of Formula (N) from the compoundof Formula (A′) can be carried out, for example, by Wittig reactionusing methyltriphenylphosphonium bromide and the like in the presence ofa base.

[0134] Metallic hydroxides, metallic hydrides, alkaline metals, metallicdialkylamides and the like can be used as the base. Specific examplesthereof include sodium hydroxide, sodium methoxide, sodium hydride,n-butyllithium, s-butyllithium, t-butyllithium, phenyllithium, potassiumhydroxide, potassium hydride, potassium t-butoxide, lithiumdiisopropylamide, sodium diisopropylamide, potassium diisopropylamide,lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassiumbistrimethylsilylamide and the like, with potassium t-butoxide beingpreferred.

[0135] Hydrocarbon-, ether-, amide- and sulfoxide-based solvents can beused as the solvent; specific examples include pentane, hexane, benzene,toluene, diethyl ether, t-butylmethyl ether, tetrahydrofuran,1,2-dimethoxyethane, 1,4-dioxane, anisole,1,3-dimethyl-2-imidazolidinone,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, dimethylsulfoxideand the like, with toluene and tetrahydrofuran being preferred.

[0136] The reaction temperature is not particularly limited unless thereaction can proceed; generally the reaction is carried out in the rangeof −50° C. to 150° C. and preferably in the range of 0 to 100° C.

[0137] (Step 2) Hydroboration-oxidation

[0138] A compound of Formula (O) is produced by hydroboration-oxidationof the compound of Formula (N).

[0139] Borane, alkylboranes and dialkylboranes can be used inhydroboration. Examples thereof include diborane, borane-tetrahydrofurancomplex, borane-dimethylsulfide complex, borane-triethylamine complex,borane-dimethylamine complex, borane-t-butylamine complex,borane-pyridine complex, disiamylborane, dithexylborane,9-borabicyclo[3,3,1]nonane and the like, with 9-borabicyclo[3,3,1]nonanebeing preferred.

[0140] Ether- and halogen-based solvents can be used as the solvent.Examples thereof include diethyl ether, t-butylmethyl ether,tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, anisole,dichloromethane, chloroform, 1,2-dichloroethane and the like, withtetrahydrofuran being preferred.

[0141] The reaction temperature is not particularly limited unless thereaction can proceed; generally the reaction is carried out in the rangeof 0 to 100° C. and preferably at room temperature. Oxidation is carriedout by hydrogen peroxide solution and the like in alkaline conditions(e.g., using sodium hydroxide solution).

[0142] (Step 3) Side chain introduction

[0143] According to a similar method as in Step 3 of I-1, Compound (O)is reacted with an alkylation agent corresponding to the side chain inthe presence of a base to give Compound (P).

[0144] (Step 4) Diene-formation at the 5,7-positions and protection.

[0145] According to a conventional method, diene-formation at the5,7-positions of Compound (P) and protection of the formed dienes arecarried out to give Compound (Q) (for example, according to the methoddescribed in JP No. 61-267550 A).

[0146] (Step 5) Deprotection of 5,7-diene moieties (deprotection 1)

[0147] According to a conventional method, the diene moieties of the5,7-positions of Compound (Q) were deprotected to give Compound (R) (forexample, according to the method described in Kubodera et al., J. Org.Chem. 1992, 57, 5019).

[0148] (Step 6) Deprotection of silyl groups (deprotection 2)

[0149] Similarly to Step 4 of I-1, the t-butyldimethylsilyl groups ofCompound (R) are removed to give Compound (S) according to aconventional method.

[0150] (Step 7) Photoreaction and thermal isomerization

[0151] Similarly to Step 5 of I-1, Compound (S) is subjected tophotoreaction and thermal isomerization to give Compound (T) accordingto a conventional method.

[0152] The order of Steps 3, 4, 5, 6 and 7 is not particularly limitedto that order; Step 6 is not carried out before Steps 3 and 4. Step 7 isnot carried out before Steps 4 and 5.

[0153] If necessary, the side chain of each intermediate may be modifiedas shown in the following scheme.

[0154] wherein TBS is a t-butyldimethylsilyl group.

[0155] In the above, the side chain is modified by reacting Compound (Q)(in which R is (CH₂)₂CON(CH₃)₂) with a base. Alkaline metal hydrides,alkaline metal alkoxides, metal dialkylamides, alkaline metals and thelike can be used as the base. Preferably sodium hydride, potassiumhydride, potassium t-butoxide, lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, methyllithium, n-butyllithium andethylmagnesium bromide and the like are used, with potassium t-butoxidebeing preferred.

[0156] Hydrocarbon-, ether- and amide-based solvents can be used as thesolvent. Specific examples thereof include benzene, toluene, diethylether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane,N,N-dimethylacetamide, N,N-dimethylformamide,1,3-dimethyl-2-imidazolidinone,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and the like. Amongthem, tetrahydrofuran, 1,2-dimethoxyethane, N,N-dimethylformamide and1,3-dimethyl-2-imidazolidinone are preferred and tetrahydrofuran is morepreferred.

[0157] The reaction temperature depends on the substance; in general,the reaction is carried out in the range of −40° C. to the boiling ordecomposition temperature of the solvent used in the reaction,preferably in the range of 0 to 100° C., and more preferably at roomtemperature.

[0158] If necessary, the side chain of each intermediate may be modifiedas shown in the following scheme.

[0159] wherein TBS is a t-butyldimethylsilyl group.

[0160] In the above, the side chain is modified by reacting Compound (R)(in which R is (CH₂)₂CON(CH₃)₂) with an alkaline metal. This reactionmay be carried out, for example, by the method described in JP No.6-72994 A, however it is not specifically limited thereto and can becarried out by conventional methods.

[0161] In each of Steps I-1, I-2 and II, each of the intermediates andfinal products can be purified and isolated by conventional means suchas silica gel chromatography, thin layer chromatography andrecrystallization.

[0162] The thus obtained vitamin D derivatives of Formula (1) are usefulas a medicine with a reduced hypercalcemic effect, as is shown in thefollowing Test examples.

[0163] The pharmaceutical composition comprising the vitamin Dderivative of the present invention may be formulated into desireddosage forms with pharmaceutically acceptable carriers, excipients,disintegrants, lubricants, binders, flavors, colorants, and the like;examples of the dosage forms include tablets, granules, fine granules,capsules, powders, injections, solutions, suspensions, emulsions,percutaneous absorption formulations, suppositories, and the like.

[0164] When the therapeutic agent for skin diseases, which contains thevitamin D derivative of the present invention as an active ingredient,is used for treating psoriasis, it may be formulated into externalpreparations such as ointments, creams and lotions.

[0165] The dosage of the therapeutic agent comprising a vitamin Dderivative of the present invention as an active ingredient can beappropriately chosen depending on the target disease, the conditions,body type, constitution, age and sex of the patient, the administrationroute, the dosage form and other factors. In general, the dosage as theactive ingredient is in the range of 0.001 μg/day to 10,000 μg/day,preferably 0.01 μg/day to 1,000 μg/day for oral administration, in therange of 0.01 μg/day to 10,000 μg/day, preferably 0.1 μg/day to 1,000μg/day for injection, and in the range of 1 μg/day to 50,000 μg/day,preferably 10 μg/day to 5,000 μg/day for external preparation, whichdoses may be administered at a time or in divided portions twice orthree times a day.

[0166] When the therapeutic agent for skin diseases containing a vitaminD derivative of the present invention as an active ingredient is usedfor treating psoriasis, topical application using external preparationsand the like is preferred; systemic application using oral formulationsor injections may be also employed.

EXAMPLES

[0167] The present invention will be described specifically by way ofthe following Examples, which in no way limit the invention. InExamples, NMR spectra were measured using tetramethylsilane orchloroform as the internal standard and unless otherwise specified,using CDCl₃ as the solvent. Mass spectra (MS) were measured by EI modeat an ionic voltage of 70 eV. Ultraviolet absorption spectra (UV) weremeasured in an ethanol solvent. Column chromatography was carried outusing silica gel (75-150 μm or 40-63 μm) and thin layer chromatographywas carried out using silica gel (1 mm, 0.5 mm or 0.25 mm thickness,each 20×20 cm).

Example 1

[0168] Synthesis of 17-acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triene

[0169] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(2,4,6-triisopropylbenzenesulfonylhydrazono)androsta-5,7-diene

[0170] 1α, 3β-Bis(tert-butyldimethylsilyloxy)-17-oxoandrosta-5,7-diene(1.64 g, 3.08 mmol) and 2,4,6-triisopropylbenzenesulfonylhydrazide (1.01g, 3.39 mmol) were dissolved in ethyl acetate (6 ml) and stirred at roomtemperature for 16 hours. The reaction mixture was concentrated underreduced pressure and the thus obtained residue was purified by columnchromatography (hexane:ethyl acetate=15:1) to give the titled compound(1.86 g, 75%). ¹H NMR δ: 7.15 (s, 2H), 6.98 (brs, 1H), 5.58 (d, J=5.8Hz, 1 H), 5.40-5.33 (m, 1H), 4.28-4.20 (m, 2H), 4.18-3.93 (m, 1H),3,70-3.63 (m, 1H), 2.95-2.74 (m, 2H), 1.30-1.22 (m, 24H), 0.88 (s, 9H),0.85 (s, 9H), 0.68 (s, 3H), 0.09 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H),0.03 (s, 3H). IR(KBr): 3232, 2956, 2860, 1600, 1462, 1426, 1384, 1372,1362, 1328, 1254, 1214, 1194, 1166, 1154, 1102, 1038, 1006, 968, 952,938, 928, 916, 878, 834, 774, 716, 666, 548cm⁻¹.

[0171] (2) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene

[0172] A solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(2,4,6-triisopropylbenzenesulfonylhydrazono)androsta-5,7-diene(32.7 mg, 0.0403 mmol) in hexane (0.8 ml) and tetramethylethylenediamine(0.16 ml) was cooled to −78° C. and 1.53M n-butyl lithium (0.106 ml,0.161 mmol) was added. After stirring at −78° C. for 2 hours, thereaction mixture was warmed to 0° C., stirred for 15 min.,paraformaldehyde (10 mg, 0.33 mmol) was added and stirred at 0° C. for 1hour then at room temperature for 1 hour. After adding brine, thereaction mixture was extracted with dichloromethane, the extract wasdried over anhydrous sodium sulfate and evaporated for removing thesolvent. The thus obtained residue was purified by column chromatography(hexane:ethyl acetate=6:1) to give the titled compound (13.6 mg, 62%).

[0173] (3) Synthesis of17-acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triene

[0174] To a solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene(4.00 g, 7.34 mmol) in tetrahydrofuran (70 ml), was added triethylamine(4.10 ml, 29.4 mmol), followed by the dropwise addition ofmethanesulfonyl chloride (1.70 ml, 22.0 mmol) at −10° C. and stirringfor 20 min. The reaction mixture was warmed to room temperature and asolution of potassium thioacetate (3.73 g, 29.4 mmol) indimethylsulfoxide (70 ml) was added. After stirring for 30 min., themixture was diluted with hexane, washed with water, the organic layerwas dried over anhydrous magnesium sulfate and evaporated for removingthe solvent. The thus obtained residue was purified by silica gel columnchromatography (hexane:ethyl acetate=15:1) to give the titled compound(3.91 g, 88%) as a colorless oil. IR(neat): 2954, 2929, 2897, 2856,1695, 1471, 1462, 1371, 1360, 1254, 1099cm⁻¹. ¹H NMR δ:0.05(s, 1H), 0.07(s, 3H), 0.07 (s, 3H), 0.11 (s, 3H),0.82 (s, 3H), 0.88 (s, 18H), 0.94(s, 3H), 2.34 (s, 3H), 2.79-2.90(m, 1H), 3.52-3.68(m, 2H), 3.68-3.73 (m,1H), 3.98-4.12 (m, 1H), 5.35-5.41 (m, 1H), 5.57-5.64 (m, 2H). MS m/z:602 (M⁺), 413 (100%). UV λ_(max), nm: 234, 261, 271, 281, 294.

Example 2

[0175] Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene

[0176] After the procedure of Step (1) of Example 1, the following stepwas carried out instead of Step (2). A solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(2,4,6-triisopropylbenzenesulfonylhydrazono)androsta-5,7-diene(91.0 mg, 0.112 mmol) in hexane (2.5 ml) and tetramethylethylenediamine(0.50 ml) was cooled to −78° C. and 1.53M n-butyl lithium (0.293 ml,0.449 mmol) was added. The reaction mixture was stirred at −78° C. for 2hours, warmed to 0° C. and stirred for 15 min., followed by the additionof acetone (0.10 ml) and stirring at 0° C. for 20 min. After addingbrine, the reaction mixture was extracted with dichloromethane; theextract was dried over anhydrous sodium sulfate and evaporated forremoving the solvent. The thus obtained residue was purified by columnchromatography (hexane:ethyl acetate=10:1) to give the titled compound(28.8 mg, 45%). ¹H NMR δ: 5.65(dd, J=2.2, 2.5 Hz, 1H), 5.61 (d, J=5.5Hz, 1H), 5.44-5.38 (m, 1H), 4.12-3.99 (m, 1H), 3.73-3.68 (m, 1H),2.90-2.80(m, 1H), 2.40-2.26 (m, 3H), 2.20-2.08 (m, 3H), 1.99-1.88 (m,1H), 1.41 (s, 6H), 0.96 (s, 3H), 0.94 (s, 3H), 0.88 (s, 18H), 0.11 (s,3H), 0.07 (s, 6H), 0.05 (s, 3H). IR(KBr): 3480, 2952, 2928, 2892, 2856,1470, 1460, 1372, 1360, 1254, 1100, 1084, 1066, 968, 878, 834, 812, 774cm⁻¹.

Example 3

[0177] Instead of Steps (1) and (2) of Example 1, the following Steps(1) and (2) were carried out.

[0178] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7-diene-(17S)-spiro-2′-oxirane

[0179] To dimethylsulfoxide (13 ml), was added sodium hydride (60% inoil, 0.2821 g, 7.06 mmol), followed by stirring at 80° C. for 1 hour.The thus obtained suspension was cooled to 0° C., diluted withtetrahydrofuran (19 ml) and a solution of trimethylsulfonium iodide(1.33 g, 6.50 mmol) in dimethylsulfoxide (9 ml) was added dropwise,followed by stirring at 0° C. for 35 min. After adding a solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17-oxoandrosta-5,7-diene (1.0 g,1.88 mmol) in tetrahydrofuran (7 ml), the mixture was stirred at roomtemperature for 14 hours. The resulting reaction mixture was poured intoa saturated aqueous ammonium chloride, extracted with ethyl acetate, theextract was washed with water and saturated brine, dried over anhydroussodium sulfate and evaporated for removing the solvent. The thusobtained residue was purified by column chromatography (hexane:ethylacetate=6:1) to give the titled compound (0.93 g, 91%) as a white foam.¹H NMR δ: 0.05 (s, 3H), 0.06 (s, 3H), 0.07 (s, 3H), 0.11 (s, 3H), 0.88(s, 3H), 0.89 (s, 3H), 2.65 (d, J=4.9 Hz, 1H), 2.93 (d,J=4.9 Hz, 1H),3.71 (brs, 1H), 3.98-4.12(m, 1H), 5.35-5.43 (m, 1H), 5.57-5.64 (m,1H).

[0180] (2) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene

[0181] To a solution of1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7-diene-(17S)-spiro-2′-oxirane(20 g, 36.7 mmol) in 1,2-dichlorobenzene (130 ml), was added aluminumisopropoxide (22 g, 108 mmol) under an argon atmosphere, followed bystirring at 130° C. for 1.5 hours. After adding Rochelle salt solution,the mixture was extracted with ethyl acetate (twice). The extracts werewashed with water, dried over anhydrous sodium sulfate and evaporated toremove the solvent. The thus obtained residue was purified by columnchromatography (hexane:ethyl acetate=6:1) to give the titled compound(10 g, 50%) as a white solid. IR(neat): 3392, 2954, 2929, 2856, 1462,1254, 1097, 1082 cm⁻¹. ¹H NMR δ: 0.05 (s, 3H), 0.07 (s, 6H), 0.11 (s,3H), 0.88 (s, 3H), 0.89 (s, 3H), 3.71 (brs, 1H), 4.00 (brs, 1H), 4.22(s, 2H), 5.40 (brs, 1H), 5.57-5.66 (m, 2H). MS m/z: 544 (M⁺), 355(100%). UV λ_(max) nm: 270, 281, 293.

Example 4

[0182] Synthesis of17-acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triene

[0183] After the procedure of Steps (1) and (2) of Example 1, thefollowing Step was carried out instead of Step (3) of Example 1.

[0184] To a solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene(100 mg, 0.183 mmol), triphenylphosphine (96.0 mg, 0.366 mmol) andimidazole (49.8 mg, 0.732 mmol) in dichloromethane (2 ml), was addedN-bromosuccinimide (65.1 mg, 0.366 mmol) at 0° C., followed by stirringat room temperature. After 1 hour, hexane was added to the mixture andwashed with water and then saturated brine. The organic layer was driedover anhydrous magnesium sulfate and evaporated under reduced pressureto remove the solvent, giving a mixture (150 mg) containing1α,3β-bis(tert-butyldimethylsilyloxy)-17-(bromomethyl)androsta-5,7,16-triene.The mixture was dissolved in acetone (1.5 ml), to which potassiumthioacetate (31.4 mg, 0.275 mmol) was added, followed by stirring for 30min. The reaction mixture was diluted with hexane, filtered and theresulting filtrate was evaporated under reduced pressure to remove thesolvent. The residue was purified by preparative thin layerchromatography (2 sheets (each 0.5 mm thickness), hexane:ethylacetate=20:1, developed once) to give the titled compound (70.2 mg, 64%)as a colorless oil.

Example 5

[0185] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(4-triethylsilyloxy-4-methylpentyloxymethyl)androsta-5,7,16-triene

[0186] To a solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene(200 mg, 0.367 mmol), sodium hydride (60% in oil, 45 mg, 1.125 mmol) and15-crown-5 (80 mg, 0.363 mmol) in tetrahydrofuran (1 ml), was added1-bromo-4-methyl-4-(triethylsilyloxy)pentane (220 mg, 0.745 mmol) atroom temperature, followed by reflux under heating for 1 hour. Thereaction solution was diluted with ethyl acetate, followed by thedropwise addition of water under cooling with ice and washing withsaturated brine. The organic layer was dried over anhydrous magnesiumsulfate. After distilling off the solvent under reduced pressure, thethus obtained residue was purified by column chromatography(hexane:ethyl acetate=15:1) to give the titled compound (278.7 mg,quant.) as a colorless oil. IR(neat): 2932, 1460, 1364, 1252, 1068, 834,774 cm⁻¹. ¹H NMR δ: 0.05 (s, 3H), 0.06 (s, 6H), 0.11 (s, 3H), 0.56 (q,J=8.0 Hz, 6H), 0.83 (s, 3H), 0.88 (s, 21H), 0.94 (t, J=8.0 Hz, 9H), 1.20(s, 6H), 2.80-2.92 (m, 1H), 3.34-3.48 (m, 2H), 3.70 (brs,, 1H), 4.01(brs, 1H), 3.99-4.13 (m, 1H), 5.36-5.43 (m, 1H), 5.61 (d, J=5.8 Hz, 1H),5.64 (s, 1H). MS m/z: 759 (M⁺+1), 73 (100%). UV λ_(max) nm: 271, 281,294.

[0187] (2) Synthesis of1α,3β-dihydroxy-17-(4-hydroxy-4-methylpentyloxymethyl)androsta-5,7,16-triene

[0188] To a solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(4-triethylsilyloxy-4-methylpentyloxymethyl)androsta-5,7,16-triene(278.7 mg, 0.367 mmol) in tetrahydrofuran (2 ml), was added a 1Mtetra-n-butylammonium fluoride tetrahydrofuran solution (3.3 ml, 3.3mmol), followed by reflux under heating for 14 hours. The reactionsolution was diluted with ethyl acetate, washed with 5% hydrochloricacid, a saturated aqueous sodium bicarbonate solution and saturatedbrine in that order, the organic layer was dried over anhydrousmagnesium sulfate and evaporated under reduced pressure to remove thesolvent. The thus obtained residue was purified by column chromatography(dichloromethane:ethanol=10:1) and preparative thin layer chromatography(4 sheets (each 0.5 mm thickness), dichloromethane:ethanol=20:1,developed twice, and then dichloromethane:ethanol=10:1, developed twice)to give the titled compound (56.3 mg, 37%) as a colorless foam.IR(neat): 3384, 2932, 1462, 1370, 1084, 1054, 944, 730 cm⁻¹. ¹H NMR δ:0.84 (s, 3H), 0.98 (s, 3H), 1.22 (s, 6H), 2.47-2.61(m, 1H), 2.73-2.86(m, 1H), 3.36-3.55 (m, 2H), 3.77 (brs, 1H), 3.94-4.16 (m, 2H), 5.40-5.50(m, 1H), 5.64 (s, 1H), 5.59-5.79 (m, 1H),. MS m/z:298(M⁺—HOCH₂CH₂CH₂C(CH₃)₂OH), 83(100%). UV λ_(max) nm: 271, 281, 293.

[0189] (3) Synthesis of1α,3β-dihydroxy-17-(4-hydroxy-4-methylpentyloxymethyl)-9,10-secoandrosta-5,7,10(19),16-tetraene

[0190]1α,3β-Dihydroxy-17-(4-hydroxy-4-methylpentyloxymethyl)androsta-5,7,16-triene(55.0 mg, 0.132 mmol) was dissolved in ethanol (200 ml). While stirringthe solution and bubbling argon thereinto at 0° C., the solution wasirradiated using a 400 W high-pressure mercury lamp with a Vycor filterfor 4.5 min. and then subjected to reflux under heating for 1.5 hours.The reaction mixture was cooled to room temperature, evaporated underreduced pressure to remove the solvent and the thus obtained residue waspurified by preparative thin layer chromatography (1 sheet (0.5 mmthickness), dichloromethane:ethanol=20:1, developed once, anddichloromethane:ethanol=10:1, developed twice; 1 sheet (0.25 mmthickness), hexane:ethyl acetate:ethanol=10:5:1, developed three times;and 1 sheet (0.25 mm thickness), dichloromethane:ethyl acetate=3:1developed once, and dichloromethane:ethyl acetate=2:1, developed twice),giving the titled compound (1.802 mg, 3%) as a colorless oil. IR(neat):3400, 2936, 1446, 1364, 1058, 730 cm⁻¹. ¹H NMR δ: 0.73 (s, 3H), 1.22 (s,6H), 2.26-2.38 (m, 1H), 2.39-2.49 (m, 1H), 2.55-2.65 (m, 1H), 2.76-2.87(m, 1H), 3.36-3.53 (m, 2H), 3.94-4.08 (m, 2H), 4.19-4.30 (m, 1H),4.40-4.48 (m, 1H), 5.01 (s, 1H), 5.34 (s, 1H), 5.60 (s, 1H), 6.09 (d,J=11.6 Hz, 1H), 6.37 (d, J=11.6 Hz, 1 H). MS m/z: 416 (M⁺), 134 (100%).UV λ_(max) nm: 263.

Example 6

[0191] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(4-ethyl-4-(triethylsilyloxy)hexyloxymethyllandrosta-5,7,16-triene

[0192]1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene(400 mg, 0.734 mmol), 1-bromo-4-ethyl-4-(triethylsilyloxy)hexane (475mg, 1.47 mmol), sodium hydride (60% in oil, 88 mg, 2.20 mmol),15-crown-5 (162 mg, 0.735 mmol) and tetrahydrofuran (1 ml) weresubjected to reaction using a procedure similar to that of Example 5(1)(reflux under heating for 1 hour), worked up and purified by columnchromatography (hexane:toluene=3:2) to give the titled compound (569 mg,98%) as a colorless oil. IR(neat): 2954, 1462, 1373, 1254, 1099, 1072cm⁻¹. ¹H NMR δ: 0.05 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.57 (q, J=7.9Hz, 6H), 0.88 (s, 9H), 0.88 (s, 9H), 0.94 (s, 3H), 0.94 (q, J=7.9 Hz,9H), 1.46 (q, J=7.6 Hz, 4H), 2.81-2.90 (m, 1H), 3.35-3.46 (m, 2H),3.69-3.73 (br, 1H), 3.97-4.11 (m, 3H), 5.36-5.42 (m, 1H), 5.57-5.62 (m,1H), 5.64 (brs, 1H). MS m/z: 654 (M³⁰-HOTBS), 73 (100%). UV λ_(max) nm:270, 281, 293.

[0193] (2) Synthesis of17-(4-ethyl-4-hydroxyhexyloxymethyl)-1α,3β-dihydroxyandrosta-5,7,16-triene1α,3β-Bis(tert-butyldimethylsilyloxy)-17-{4-ethyl-4-(triethylsilyloxy)hexyloxymethyl}androsta-5,7,16-triene(559 mg, 0.710 mmol) and a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (6 ml) were subjected to reaction using aprocedure similar to that of Example 5(2) (4 hours), worked up andpurified by column chromatography (ethyl acetate:dichloromethane=4:1 andthen ethyl acetate) to give the titled compound (292 mg, 93%) as acolorless foam. IR(neat): 3369, 2964, 2937, 2879, 2854, 1460, 1369,1149, 1036 cm⁻¹. ¹H NMR δ: 0.89 (s, 3H), 0.99 (s, 3H), 1.47 (q, J=7.6Hz, 4H), 2.74-2.85 (m, 1H), 3.39-3.50 (m, 2H), 3.79 (brs, 1H), 3.96-4.17(m, 3H), 5.43-5.49 (m, 1H), 5.65 (brs, 1H), 5.75 (brd, J=5.9 Hz, 1H). MSm/z: 444 (M⁺), 69(100%). UV λ_(max) nm: 271, 281, 293.

[0194] (3) Synthesis of17-(4-ethyl-4-hydroxyhexyloxymethyl)-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene

[0195]17-(4-ethyl-4-hydroxyhexyloxymethyl)-1α,3β-dihydroxyandrosta-5,7,16-triene(261 mg, 0.587 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 12min. 15 sec., reflux under heating for 2 hours) and purified bypreparative thin layer chromatography (7 sheets (each 0.5 mm thickness),dichloromethane:ethanol=10:1, developed twice; 1 sheet (0.5 mmthickness), toluene:ethyl acetate=1:1, developed three times; and then 1sheet (0.5 mm thickness), dichloromethane:ethyl acetate=1:1, developedtwice) to give the titled compound (2.48 mg, 1%) as a colorless glassysubstance. IR(neat): 3367, 2931, 2879, 2850, 1456, 1367, 1350, 1055cm⁻¹. ¹H NMR δ:0.73(s,3H),1.47(q,J=7.3Hz,4H),2.77-2.88(m,1H), 3.39-3.50(m, 2H), 3.93-4.07 (m, 2H), 4.17-4.30 (br, 1H), 4.40-4.49 (m, 1H), 5.01(brs, 1H), 5.34 (brs, 1H), 5.60 (brs, 1H), 6.10 (d, J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). MS m/z: 426 (M⁺-H₂O), 134 (100%). UV λ_(max) nm:264.

Example 7

[0196] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(5-triethylsilyloxy-5-methylhexyloxymethyl)androsta-5,7,16-triene

[0197]1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene(200 mg, 0.367 mmol), 1-bromo-5-triethylsilyloxy-5-methylhexane (227 mg,0.734 mmol), sodium hydride (60% in oil, 44 mg, 1.10 mmol), 15-crown-5(81 mg, 0.368 mmol) and tetrahydrofuran (0.5 ml) were subjected toreaction using a procedure similar to that of Example 5(1) (reflux underheating for 1 hour), worked up and purified by column chromatography(hexane:toluene=3:2) to give the titled compound (270 mg, 95%) as acolorless oil. IR(neat): 2954, 2931, 2858, 1462, 1362, 1254, 1099, 1080cm⁻¹. ¹H NMR δ: 0.05 (s, 3 H), 0.06 (s, 6 H), 0.11 (s, 3H), 0.56 (q,J=7.9 Hz, 6H), 0.84 (s, 3H), 0.88 (s, 9H), 0.88 (s,9H), 0.94 (s, 3H),0.94 (q, J=7.9 Hz, 9H), 1.18 (s, 6H), 2.80-2.91 (m, 1H), 3.37-3.47 (m,2H), 3.71 (brs, 1H), 3.96-4.11 (m, 3H), 5.36-5.41 (m, 1H), 5.57-5.62 (m,1H), 5.64 (brs, 1H). MS m/z: 773 (M⁺+1), 73 (100%). UV λ_(max) nm: 270,281, 293.

[0198] (2) Synthesis of1α,3β-dihydroxy-17-(5-hydroxy-5-methylhexyloxymethyl)androsta-5,7,16-triene

[0199]1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(5-triethylsilyloxy-5-methylhexyloxymethyl)androsta-5,7,16-triene(420 mg, 0.543 mmol) and a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (6 ml) were subjected to reaction using aprocedure similar to that of Example 5(2) (4 hours), worked up andpurified by column chromatography (ethyl acetate:dichloromethane=4:1) togive the titled compound (220 mg, 94%) as a colorless foam. IR(neat):3360, 2964, 2937, 2862, 1462, 1369, 1198, 1059 cm⁻¹. ¹H NMR δ:0.84 (s,3H), 0.99 (s, 3H), 1.21 (s, 6H), 3.38-3.50 (m, 1H), 3.80 (brs, 1H),3.96-4.18 (m, 3H), 5.43-5.51 (m, 1H), 5.65 (brs, 1H), 5.73-5.79 (m, 1H).MS m/z: 412 (M⁺-H₂O), 59 (100%). UV λ_(max) nm: 271, 281, 293.

[0200] (3) Synthesis of1α,3β-dihydroxy-17-(5-hydroxy-5-methylhexyloxymethyl)-9,10-secoandrosta-5,7,10(19),16-tetraene

[0201]1α,3β-Dihydroxy-17-(5-hydroxy-5-methylhexyloxymethyl)androsta-5,7,16-triene(201 mg, 0.467 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 11min. 15 sec., reflux under heating for 2 hours) and purified bypreparative thin layer chromatography (5 sheets (each 0.5 mm thickness),dichloromethane:ethanol=10:1, developed twice; 2 sheets (each 0.5 mmthickness), toluene:ethyl acetate=1:1, developed three times; and 2sheets (each 0.5 mm thickness), dichloromethane:ethyl acetate=1:1,developed three times) to give the titled compound (19.3 mg, 10%) as acolorless glassy substance. IR(neat): 3369, 2935, 2864, 2848, 1435,1367, 1209, 1157, 1059 cm⁻¹. ¹H NMR δ: 0.74 (s, 3H), 1.21 (s, 6H),2.76-2.87 (m, 1H), 3.36-3.50 (m, 2H), 3.93-4.07 (m, 2H), 4.18-4.29 (br,1H), 4.39-4.49 (br, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.60 (brs, 1H),6.10 (d, J=11.2 Hz, 1H), 6.37 (d, J=11.2 Hz, 1H). MS m/z: 430 (M⁺), 134(100%). UV λ_(max) nm: 264.

Example 8

[0202] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(4-triethylsilyloxy-4-methyl-2-pentynyloxymethyl)androsta-5,7,16-triene

[0203]1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene(200 mg, 0.367 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-2-pentyne (216mg, 0.741 mmol), sodium hydride (60% in oil, 44 mg, 1.10 mmol)15-crown-5 (81 mg, 0.368 mmol) and tetrahydrofuran (1 ml) were subjectedto reaction using a procedure similar to that of Example 5(1) (at roomtemperature 17 hours), worked up and purified by column chromatography(hexane:toluene=3:2) to give the titled compound (183 mg, 66%) as a paleyellow oil. IR(neat): 2954, 2931, 2877, 2856, 1458, 1375, 1360, 1252,1163, 1082, 1038 cm⁻¹. ¹H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s,3H), 0.67 (q, J=7.9 Hz, 6H), 0.84 (s, 3H), 0.88 (s, 9H), 0.89 (s, 9H),0.96 (t, J=7.6 Hz, 9H), 1.49 (s, 6H), 2.80-2.92 (m, 1H), 3.98-4.10 (br,1H), 4.10 (brs, 2H), 4.16 (s, 2H), 5.35-5.43 (m, 1H), 5.61 (brd, J=5.3Hz, 1H), 5.69(brs, 1H). MS m/z: 754 (M⁺), 73 (100%). UV λ_(max) nm: 271,282, 294.

[0204] (2) Synthesis of1α,3β-dihydroxy-17-(4-hydroxy-4-methyl-2-pentynyloxymethyl)androsta-5,7,16-triene

[0205]1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(4-triethylsilyloxy-4-methyl-2-pentynyloxymethyl)androsta-5,7,16-triene(480 mg, 0.635 mmol) and 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (6 ml) were subjected to reaction using aprocedure similar to that of Example 5(2) (4 hours), worked up andpurified by column chromatography (ethyl acetate:dichloromethane=4:1followed by ethyl acetate) to give the titled compound (240 mg, 92%) asa pale yellow foam. IR(neat): 3330, 2974, 2933, 2852, 1458, 1369, 1234,1167, 1059 cm⁻¹. ¹H NMR δ: 0.85 (s, 3H), 0.99 (s, 3H), 1.53 (s, 6H),2.73-2.87 (m, 1H), 3.76-3.82 (br, 1H), 4.01-4.17 (m, 4H), 5.43-5.50 (m,1H), 5.70 (brs, 1H), 5.75 (dd, J=5.6, 2.0 Hz, 1H). MS m/z: 412 (M⁺), 105(100%). UV λ_(max) nm: 271, 282, 294.

[0206] (3) Synthesis of1α,3β-dihydroxy-17-(4-hydroxy-4-methyl-2-pentynyloxymethyl)-9,10-secoandrosta-5,7,10(19),16-tetraene

[0207]1α,3β-Dihydroxy-17-(4-hydroxy-4-methyl-2-pentynyloxymethyl)androsta-5,7,16-triene(143 mg, 0.347 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 7min., reflux under heating for 2 hours) and purified by preparative thinlayer chromatography (3 sheets (each 0.5 mm thickness),dichloromethane:ethanol=10:1, developed twice; 2 sheets (each 0.5 mmthickness), toluene:ethyl acetate=1:1, developed twice; and 2 sheets(each 0.5 mm thickness), dichloromethane:ethyl acetate=1:1, developedthree times) to give the titled compound (6.00 mg, 4%) as a colorlessglassy substance. IR(neat): 3363, 2978, 2931, 2848, 1437, 1363, 1234,1167, 1061 cm⁻¹. ¹H NMR δ: 0.74 (s, 3H), 1.53 (s, 6H), 2.76-2.87 (m,1H), 4.08 (brs, 2H), 4.15 (brs, 2H), 4.18-4.29 (m, 1H), 4.38-4.50 (m,1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.66 (brs, 1H), 6.10 (d, J=11.2 Hz,1H), 6.37 (d, J=11.2 Hz, 1H). MS m/z: 412 (M⁺), 134 (100%). UV λ_(max)nm: 264.

Example 9

[0208] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-{4-triethylsilyloxy-4-methyl-(2E)-pentenyloxymethyl}androsta-5,7,16-triene

[0209]1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene(400 mg, 0.734 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-(2E)-pentene(431 mg, 1.47 mmol), sodium hydride (60% in oil, 88 mg, 2.20 mmol),15-crown-5 (162 mg, 0.735 mmol) and tetrahydrofuran (1 ml) weresubjected to reaction using a procedure similar to that of Example 5(1)(at room temperature for 2 hours), worked up and purified by columnchromatography (hexane:toluene=3:2) to give the titled compound (556 mg,100%) as a colorless oil. IR(neat): 2954, 2929, 2856, 1462, 1371, 1360,1254, 1149, 1099, 1074, 1051 cm⁻¹. ¹H NMR δ: 0.05 (s, 3H), 0.07 (s, 6H),0.11 (s, 3H), 0.57 (q, J=7.9 Hz, 6H), 0.84 (s, 3H), 0.88 (s, 9H), 0.88(s, 9H), 0.94 (s, 3H), 0.94 (t, J=7.9 Hz, 9H), 1.31 (s, 6H), 2.79-2.92(m, 1H), 3.71 (brs, 1H), 3.89-4.11 (m, 5H), 5.35-5.41 (m, 1H), 5.55-5.85(m,4H). MS m/z: 756 (M⁺), 73 (100%). UV λ_(max) nm: 271, 282, 294.

[0210] (2) Synthesis of1α,3β-dihydroxy-17-(4-hydroxy-4-methyl-(2E)-pentenyloxymethyl)androsta-5,7,16-triene

[0211]1α,3β-Bis(tert-butyldimethylsilyloxy)-17-{4-triethylsilyloxy-4-methyl-(2E)-pentenyloxymethyl}androsta-5,7,16-triene(550 mg, 0.726 mmol) and a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (7 ml) were subjected to reaction using aprocedure similar to that of Example 5(2) (4 hours), worked up andpurified by column chromatography (using ethylacetate:dichloromethane=4:1 and then ethyl acetate) to give the titledcompound (238 mg, 79%) as a colorless foam. IR(neat): 3371, 2970, 2931,2852, 1458, 1369, 1232, 1151, 1113, 1055 cm⁻¹. ¹H NMR δ: 0.85 (s, 3H),0.99 (s, 3H), 1.33 (s, 6H), 2.73-2.87 (m, 1H), 3.78 (brs, 1H), 3.89-4.14(m, 4H), 5.43-5.50 (m, 1H), 5.62-5.92 (m, 4H). MS m/z: 396 (M⁺-H₂O), 55(100%). UV λ_(max) nm: 271, 281, 293.

[0212] (3) Synthesis of1α,3β-dihydroxy-17-{4-hydroxy-4-methyl-(2E)-pentenyloxymethyl}-9,10-secoandrosta-5,7,10(19),16-tetraene

[0213]1α,3β-Dihydroxy-17-{4-hydroxy-4-methyl-(2E)-pentenyloxymethyl}androsta-5,7,16-triene(210 mg, 0.507 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 11min. 30 sec, reflux under heating for 2 hours) and purified bypreparative thin layer chromatography (4 sheets (each 0.5 mm thickness),dichloromethane:ethanol=10:1, developed twice; 2 sheets (each 0.5 mmthickness), toluene:ethyl acetate=1:1, developed three times; and 1sheet (0.5 mm thickness), dichloromethane:ethyl acetate 1:1, developedtwice) to give the titled compound (6.42 mg, 3%) as a colorless glassysubstance. IR(neat): 3370, 2970, 2929, 2848, 1446, 1367, 1211, 1147,1111, 1055 cm⁻¹. ¹H NMR δ: 0.74 (s, 3H), 1.33 (s, 6H), 2.76-2.86 (m,1H), 3.97 (d, J=5.6 Hz, 2H), 4.02 (brs, 2H), 4.15-4.30 (m, 1H),4.39-4.49(m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.62 (brs, 1H),5.69-5.93 (m,2H), 6.11 (d, J=11.2 Hz, 1H), 6.37 (d, J=11.2 Hz, 1H). MS m/z: 396(M⁺-H₂O), 91 (100%). UV λ_(max) nm: 263.

Example 10

[0214] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-{4-ethyl-4-triethylsilyloxy-(2E)-hexenyloxymethyl}androsta-5,7,16-triene

[0215]1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene(500 mg, 0.917 mmol), 1-bromo-4-ethyl-4-triethylsilyloxy-(2E)-hexene(0.59 g, 1.83 mmol), sodium hydride (60% in oil, 0.11 g, 2.75 mmol),15-crown-5 (0.18 ml, 0.917 mmol) and tetrahydrofuran (1.2 ml) weresubjected to reaction using a procedure similar to that of Example 5(1)(2 hours) and worked up to give a mixture (540 mg) containing the titledcompound.

[0216] (2) Synthesis of17-{4-ethyl-4-hydroxy-(2E)-hexenyloxymethyl}1α,3β-dihydroxyandrosta-5,7,16-triene

[0217] The mixture (540 mg) containing the1α,3β-bis(tert-butyldimethylsilyloxy)-17-{4-ethyl-4-triethylsilyloxy-(2E)-hexenyloxymethyl}androsta-5,7,16-trieneobtained in Example 10(1) and a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (7 ml) were subjected to reaction using aprocedure similar to that of Example 5(2) (3 hours), worked up andpurified by column chromatography (dichloromethane:ethyl acetate=1:4) togive the titled compound (222 mg, 73%) as a white foam. ¹H NMR δ: 0.84(s, 3H), 0.87 (t, J=7.6 Hz, 6H), 3.78 (brs, 1H), 3.93-4.15 (m, 5H), 5.46(brs, 1H), 5.63-5.79 (m, 4H). MS m/z: 424 (M⁺-H₂O), 57 (100%).

[0218] (3) Synthesis of17-{4-ethyl-4-hydroxy-(2E)-hexenyloxymethyl}1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19)16-tetraene17-{4-Ethyl-4-hydroxy-(2E)-hexenyloxymethyl}-1α,3β-dihydroxyandrosta-5,7,16-triene(0.222 g, 0.502 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 11min. 45 sec., reflux under heating for 2 hours) and purified bypreparative thin layer chromatography (10 sheets (each 0.5 mmthickness), dichloromethane:ethanol 9:1, developed once; and 5 sheets(each 0.5 mm thickness), ethyl acetate:toluene=1:1, developed threetimes) to give the titled compound (3.65 mg, 2%) as a colorless oil.IR(neat): 3421, 2966, 2933, 1653, 1047 cm⁻¹. ¹H NMR δ: 0.74 (s, 3H),0.86 (t, J=7.6 Hz, 6H), 4.00 (brs, 2H), 4.01 (brs, 2H), 4.23 (brs, 1H),4.44 (brs, 1H), 5.03 (s, 1H), 5.34 (s, 1H), 5.62 (s, 1H), 5.68-5.74 (m,2H), 6.10 (d, J=11.2 Hz, 1H), 6.37 (d, J=11.2 Hz, 1H). MS m/z: 424(M⁺-H₂O), 57 (100%). UV λ_(max) nm: 264.

Example 11

[0219] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(4-ethyl-4-triethylsilyloxy-2-hexynyloxymethyl)androsta-5,7,16-triene

[0220]1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene(1.0 g, 1.84 mmol), 1-bromo-4-ethyl-4-triethylsilyloxy-2-hexyne (1.172g, 3.70 mmol), sodium hydride (60% in oil, 0.22 g, 5.51 mmol),15-crown-5 (0.36 ml, 1.84 mmol) and tetrahydrofuran (2.5 ml) weresubjected to reaction using a procedure similar to that of Example 5(1)(2 hours) and worked up to give a mixture (1.32 g) containing the titledcompound.

[0221] (2) Synthesis of17-(4-ethyl-4-hydroxy-2-hexynyloxymethyl)-1α,3β-dihydroxyandrosta-5,7,16-triene

[0222] The mixture (1.0 g) containing the1α,3β-bis(tert-butyldimethylsilyloxy)-17-(4-ethyl-4-triethylsilyloxy-2-hexynyloxymethyl)androsta-5,7,16-trieneobtained in the above (1) and a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (12 ml) were subjected to reaction using aprocedure similar to that of Example 5(2) (3 hours), worked up andpurified by column chromatography (dichloromethane:ethyl acetate=1:4) togive a fraction (0.46 g) containing the titled compound.

[0223] (3) Synthesis of17-(4-ethyl-4-hydroxy-2-hexynyloxymethyl)-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene

[0224] The fraction (0.17 g) containing the17-(4-ethyl-4-hydroxy-2-hexynyloxymethyl)-1α,3β-dihydroxyandrosta-5,7,16-trieneobtained in the above (2) and ethanol (200 ml) were subjected toreaction using a procedure similar to that of Example 5(3) (irradiationfor 9 min., reflux under heating for 2 hours) and purified bypreparative thin layer chromatography (8 sheets (each 0.5 mm thickness),dichloromethane:ethanol=10:1, developed once; and 5 sheets (each 0.5 mmthickness), ethyl acetate:toluene=1:1, developed once) to give thetitled compound (2.62 mg, 2%) as a colorless oil. IR(neat): 3384, 2966,2931, 1716, 1458, 1373, 1240, 1053 cm⁻¹. ¹H NMR δ: 0.74 (s, 3H), 1.04(t, J=7.6 Hz, 6H), 4.10 (brs, 2H), 4.18 (s, 2H), 4.46 (brs, 1H), 5.01(s, 1H), 5.34 (s, 1H), 5.65 (s, 1H), 6.10 (d, J=11.2 Hz, 1H), 6.37 (d,J=11.2 Hz, 1H). MS m/z: 422 (M⁺-H₂O), 57 (100%). UV λ_(max) nm: 261.

Example 12

[0225] Synthesis of1α,3β-dihydroxy-20-(4-hydroxy-4-methylpentyloxy)-20-methyl-9,10-secopregna-5,7,10(19),16-tetraene

[0226]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene(100 mg, 0.17 mmol), sodium hydride (60% in oil, 41 mg, 1.01 mmol),tetrahydrofuran (3.0 ml), 15-crown-5 (37 mg, 0.17 mmol) and1-bromo-4-methyl-4-(triethylsilyloxy)pentane (306 mg, 1.04 mmol) weresubjected to reaction using a procedure similar to that of Example 5(1),worked up and purified by preparative thin layer chromatography (4sheets (each 1 mm thickness), hexane:toluene=1:1) to give a compound(133 mg) as white powder.

[0227] Then, the compound (196 mg), tetrahydrofuran (10.0 ml) and a 1Mtetra-n-butylammonium fluoride tetrahydrofuran solution (3.8 ml) weresubjected to reaction using a procedure similar to that of Example 5(2)(2 hours), worked up and purified by preparative thin layerchromatography (3 sheets (each 1.0 mm thickness), dichloromethane:ethylacetate=2:8) to give a compound (111 mg) as a yellow oil.

[0228] Then the compound (111 mg) and ethanol (200 ml) were subjected toreaction using a procedure similar to that of Example 5(3) (irradiationfor 7 min. 30 sec., reflux under heating for 2 hours) and purified bypreparative thin layer chromatography (5 sheets (each 0.5 mm thickness),dichloromethane:ethanol=20:1, developed twice; 2 sheets (each 0.5 mmthickness), hexane:ethyl acetate:ethanol=3:7:0.5, developed twice; and 1sheet (0.5 mm thickness), toluene:ethyl acetate=1:4, developed twice) togive the titled compound (7.789 mg, 7.02%, in three steps) as acolorless oil. IR(neat): 3340, 2970, 2933, 2871, 1365, 1155, 1055 cm⁻¹.¹H NMR δ: 0.84 (s, 3H), 1.22 (s, 6H), 1.34 (s, 3H), 1.35 (s, 3H),2.55-2.66 (m, 1H), 2.75-2.85 (m, 1H), 3.23-3.34 (m, 2H), 4.15-4.30 (m,1H), 4.39-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.61 (brs, 1H),6.11 (d, J=11.2 Hz, 1H), 6.38 (d, J=11.2 Hz, 1H). MS m/z: 326(M⁺—HO(CH₂)₃CMe₂OH), 59 (100%). UV λ_(max) nm: 266.

Example 13

[0229] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-20-{4-ethyl-4-(triethylsilyloxy)hexyloxy}-20-methylpregna-5,7,16-triene

[0230]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene(100 mg, 0.175 mmol), 1-bromo-4-ethyl-4-(triethylsilyloxy)hexane (225mg, 0.696 mmol), sodium hydride (60% in oil, 42 mg, 1.05 mmol),15-crown-5 (38 mg, 0.173 mmol) and tetrahydrofuran (3 ml) were subjectedto reaction using a procedure similar to that of Example 5(1) (refluxunder heating for 3 hours), worked up and purified by columnchromatography (hexane:toluene=2:1) to give the titled compound (143 mg,100%) as a colorless solid. IR(neat): 2954, 2935, 2879, 2856, 1458,1375, 1254, 1151, 1066 cm⁻¹. ¹H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11(s, 3H), 0.56 (q, J=7.6 Hz, 6H), 0.82 (q, J=6.9 Hz, 6H), 0.88 (s, 18H),1.33 (s, 3H), 1.34 (s, 3H), 1.45 (q, J=7.6 Hz, 4H), 2.78-2.90 (m, 1H),3.19 (t, J=6.9 Hz, 2H), 3.71 (brs, 1H), 3.97-4.14 (m, 1H), 5.36-5.43 (m,1H), 5.58-5.65 (m, 2H). MS m/z: 815 (M⁺+1), 73 (100%). UV λ_(max) nm:271, 282, 294.

[0231] (2) Synthesis of1α,3β-dihydroxy-20-(4-ethyl-4-hydroxyhexyloxy)-20-methylpregna-5,7,16-triene

[0232]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-(4-ethyl-4-(triethylsilyloxy)hexyloxy)-20-methylpregna-5,7,16-triene(140 mg, 0.172 mmol) and a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (3 ml) were subjected to reaction using aprocedure similar to that of Example 5(2) (3 hours), worked up andpurified by column chromatography (ethyl acetate) to give the titledcompound (81 mg, 100%) as a colorless foam. IR(neat): 3363, 2966, 2935,2879, 1458, 1236, 1236, 1151, 1038 cm⁻¹. ¹H NMR δ: 0.81-0.90 (m, 6H),0.95 (s, 3H), 0.98 (s, 3H), 1.35 (s, 3H), 1.37 (s, 1H), 2.72-2.83 (m,1H), 3.25 (t, J=5.9 Hz, 2H), 3.79 (brs, 1H), 3.99-4.16 (m, 1H),5.43-5.50 (m, 1H), 5.62-5.66 (m, 1H), 5.76 (brd, J=5.3 Hz, 1H). MS m/z:326 (M⁺—HO(CH₂)₃C(C₂H₅)₂OH), 57 (100%). UV λ_(max) nm: 271, 282, 293.

[0233] (3) Synthesis of1α,3β-dihydroxy-20-(4-ethyl-4-hydroxyhexyloxy)-20-methyl-9,10-secopregna-5,7,10(19),16-tetraene

[0234]1α,3β-Dihydroxy-20-(4-ethyl-4-hydroxyhexyloxy)-20-methylpregna-5,7,16-triene(81 mg, 0.587 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 5min., reflux under heating for 2 hours) and purified by preparative thinlayer chromatography (3 sheets (each 0.5 mm thickness),dichloromethane:ethanol=10:1, developed twice; and 1 sheet (0.5 mmthickness), toluene:ethyl acetate=9:11, developed three times) to givethe titled compound (7.34 mg, 9%) as a colorless glassy substance.IR(neat): 3369, 2966, 2933, 2879, 1452, 1367, 1242, 1149, 1055 cm⁻¹. ¹HNMR δ: 0.81-0.91 (m, 9H), 1.34 (s, 3H), 1.35 (s, 1H), 2.76-2.86 (m, 1H),3.27 (t, J=6.3 Hz, 2H), 4.17-4.30 (m, 1H), 4.39-4.51 (br, 1H), 5.01(brs, 1H), 5.34 (brs, 1H), 5.60 (brs, 1H), 6.11 (d, J=11.2 Hz, 1H), 6.38(d, J=11.2 Hz, 1H). MS m/z: 326 (M⁺—HO(CH₂)₃C(C₂H₅)₂OH), 57 (100%). UVλ_(max) nm: 264.

Example 14

[0235] Synthesis of1α,3β-dihydroxy-20-(5-hydroxy-5-methylhexyloxy)-20-methyl-9,10-secopregna-5,7,10(19),16-tetraene

[0236]1α,3β-bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene(200 mg, 0.34 mmol), sodium hydride (60% in oil, 82 mg, 2.02 mmol),tetrahydrofuran (6.0 ml), 15-crown-5 (74 mg, 0.34 mmol) and1-bromo-5-methyl-5-(triethylsilyloxy)hexane (642 mg, 2.08 mmol) weresubjected to reaction using a procedure similar to that of Example 5(1),worked up and purified by preparative thin layer chromatography (5sheets (each 1 mm thickness), hexane:toluene=1:1) to give a compound(247 mg) as a yellow oil.

[0237] Then the compound (247 mg), tetrahydrofuran (12.0 ml) and a 1Mtetra-n-butylammonium fluoride tetrahydrofuran solution (4.7 ml) weresubjected to reaction using a procedure similar to that of Example 5(2)(2 hours), worked up and purified by preparative thin layerchromatography (3 sheets (each 1.0 mm thickness), dichloromethane:ethylacetate=2:8) to give a compound (92 mg) as a yellow oil.

[0238] The compound (92 mg) and ethanol (200 ml) were subjected toreaction using a procedure similar to that of Example 5(3) (irradiationfor 5 min. 15 sec., reflux under heating for 2 hours) and purified bypreparative thin layer chromatography (3 sheets (each 0.5 mm thickness),dichloromethane:ethanol=20:1, developed three times; and 1 sheet (0.5 mmthickness), toluene:ethyl acetate=1:4, developed three times) to givethe titled compound (5.848 mg, 3.74%, in three steps) as a colorlessoil. IR(neat): 3336, 2968, 2933, 2866, 1437, 1362, 1153, 1059 cm⁻¹. ¹HNMR δ: 0.84 (s, 3H), 1.21 (s, 6H), 1.33 (s, 3H), 1.34 (s, 3H), 2.54-2.65(m, 1H), 2.75-2.84 (m, 1H), 3.25 (t, J=6.6 Hz, 2H), 4.17-4.30 (m, 1H),4.39-4.49 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.58 (brs, 1H), 6.11(d, J=11.2 Hz, 1H), 6.38 (d, J=11.2 Hz, 1H). MS m/z: 326(M⁺—HO(CH₂)₄CMe₂OH), 59 (100%). UV λ_(max) nm: 265.

Example 15

[0239] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-20-(4-triethylsilyloxy-4-methyl-2-pentynyloxy)-20-methylpregna-5,7,16-triene

[0240]1α,3β-Bis(tert-Butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene(100 mg, 0.175 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-2-pentyne (203mg, 0.697 mmol), sodium hydride (60% in oil, 42 mg, 1.05 mmol),15-crown-5 (38 mg, 0.173 mmol) and tetrahydrofuran (3 ml) were reactedusing a procedure similar to that of Example 5 (1) (reflux under heatingfor 17 hours), worked-up and purified by column chromatography(hexane:toluene=2:1) to give the titled compound (85 mg, 62%) as acolorless oil. IR(neat): 2954, 2933, 2877, 2856, 1462, 1377, 1252, 1161,1097, 1080, 1041, 1007 cm⁻¹. ¹H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11(s, 3H), 0.66 (q, J=7.9 Hz, 6H), 0.89 (s, 18H), 0.94 (s, 3H), 0.96 (t,J=7.6 Hz, 9H), 1.38 (s, 3H), 1.39 (s, 3H),1.46 (s, 6H), 2.78-2.89 (m,1H), 3.71 (brs, 1H), 3.95 (s, 2H), 3.98-4.14 (m, 1H), 5.36-5.43 (m, 1H),5.61 (d, J=5.6 Hz, 1H), 5.69 (brs, 1H). MS m/z: 783 (M⁺+1), 73 (100%).UV λ_(max) nm: 271, 282, 294.

[0241] (2) Synthesis of1α,3β-dihydroxy-20-(4-hydroxy-4-methyl-2-pentynyloxy)-20-methylpregna-5,7,16-triene

[0242]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-(4-triethylsilyloxy-4-methyl-2-pentynyloxy)-20-methylpregna-5,7,16-triene(82 mg, 0.105 mmol) and a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (3 ml) were subjected to reaction using aprocedure similar to that of Example 5(2) (3 hours), worked up andpurified by column chromatography (ethyl acetate) to give the titledcompound (51 mg, quantitative) as a colorless foam. IR(neat): 3376,2976, 2931, 2860, 1369, 1236, 1147, 1061, 1039 cm⁻¹. ¹H NMR δ: 0.96 (s,3H), 0.98 (s, 3H), 1.38 (s, 3H), 1.40 (s, 3H), 1.50 (s, 6H), 2.71-2.85(m, 1H), 3.78 (brs, 1H), 3.96 (s, 2H), 4.00-4.17 (m, 1H), 5.41-5.49 (m,1H), 5.66-5.78 (m, 2H). MS m/z: 440 (M⁺), 105 (100%). UV λ_(max) nm:271, 282, 294.

[0243] (3) Synthesis of1α,3β-dihydroxy-20-(4-hydroxy-4-methyl-2-pentynyloxy)-20-methyl-9,10-secopregna-5,7,10(19),16-tetraene

[0244]1α,3β-Dihydroxy-20-(4-hydroxy-4-methyl-2-pentynyloxy)-20-methylpregna-5,7,16-triene(48 mg, 0.109 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 4min. 30 sec., reflux under heating for 2 hours) and purified bypreparative thin layer chromatography (2 sheets (each 0.5 mm thickness),dichloromethane:ethanol=10:1, developed twice; and 1 sheet (0.5 mmthickness), toluene:ethyl acetate=5:6, developed twice) to give thetitled compound as a colorless glassy substance (0.640 mg, 1%).IR(neat): 3378, 1462, 1362, 1240, 1144, 1066, 1030 cm⁻¹. ¹H NMR δ: 0.85(s, 3H), 1.38 (brs, 6H), 1.51 (s, 6H), 2.77-2.87 (m, 1H), 3.97 (s, 2H),4.17-4.30 (m, 1H), 4.39-4.50 (br, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H),5.65-5.69 (m, 1H), 6.11 (d, J=11.2 Hz, 1H), 6.38 (d, J=11.2 Hz, 1H). MSm/z: 326 (M⁺—HOCH₂CCC(CH₃)₂OH), 55 (100%). UV λ_(max) nm: 263.

Example 16

[0245] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-20-{4-triethylsilyloxy-4-methyl-(2E)-pentenyloxy}-20-methylpregna-5,7,16-triene

[0246]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene(103 mg, 0.180 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-(2E)-pentene(211 mg, 0.719 mmol), sodium hydride (60% in oil, 43 mg, 1.08 mmol),15-crown-5 (40 mg, 0.182 mmol) and tetrahydrofuran (3 ml) were subjectedto reaction using a procedure similar to that of Example 5(1) (refluxunder heating for 6 hours), worked up and purified by columnchromatography (hexane:toluene=2:1) to give the titled compound (140 mg,99%) as a colorless solid. IR(neat): 2954, 2927, 2877, 2856, 1458, 1375,1254, 1149, 1109, 1084, 1041 cm⁻¹. ¹H NMR δ: 0.05 (s, 3H), 0.06 (s, 6H),0.11 (s, 3H), 0.50-0.63 (m, 6H), 0.88 (s, 18H), 1.29 (brs, 3H), 1.31 (s,3H), 2.78-2.89 (m, 1H), 3.68-3.74 (br, 1H), 3.77 (d, J=5.3 Hz, 1H), 3.96(d, J=5.3 Hz, 1H), 3.97-4.12 (m, 1H), 5.37-5.43 (m, 1H), 5.54-5.84 (m,4H). MS m/z: 784 (M⁺), 73 (100%). UV λ_(max) nm: 271, 282, 294.

[0247] (2) Synthesis of1α,3β-dihydroxy-20-{4-hydroxy-4-methyl-(2E)-pentenyloxy}-20-methylpregna-5,7,16-triene

[0248]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-{4-triethylsilyloxy-4-methyl-(2E)-pentenyloxy}-20-methylpregna-5,7,16-triene(136 mg, 0.173 mmol) and a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (5 ml) were subjected to reaction using aprocedure similar to that of Example 5(2) (3 hours), worked up andpurified by column chromatography (ethyl acetate) to give the titledcompound (74 mg, 97%) as a colorless foam. IR(neat): 3400, 2970, 2929,2858, 1653, 1369, 1279, 1234, 1149, 1039 cm⁻¹. ¹H NMR δ: 0.96 (s, 3H),0.98 (s, 3H), 1.32 (s, 6H)., 1.37 (s, 3H), 1.39 (s, 3H), 2.73-2.82 (m,1H), 3.76-3.83 (m, 3H), 4.00-4.16 (m, 1H), 5.44-5.49 (m, 1H), 5.66-5.88(m, 4H). MS m/z: 424 (M+—H₂O), 59 (100%). UV λ_(max) nm: 271, 282, 294.

[0249] (3) Synthesis of1α,3β-dihydroxy-20-(4-hydroxy-4-methyl-(2E)-pentenyloxyl-20-methyl-9,10-secopregna-5,7,10(19).16-tetraene

[0250]1α,3β-Dihydroxy-20-{4-hydroxy-4-methyl-(2E)-pentenyloxy}-20-methylpregna-5,7,16-triene(70 mg, 0.158 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 5min., reflux under heating for 2 hours) and purified by preparative thinlayer chromatography (2 sheets (each 0.5 mm thickness),dichloromethane:ethanol=10:1, developed twice; 1 sheet (0.5 mmthickness), toluene:ethyl acetate=5:6, developed twice; and 1 sheet (0.5mm thickness), hexane:ethyl acetate:ethanol=10:10:1, developed threetimes) to give the titled compound (6.80 mg, 10%) as a colorless glassysubstance. IR(neat): 3359, 2972, 2931, 2852, 1458, 1367, 1240, 1146,1053 cm⁻¹. ¹H NMR δ: 0.85 (s, 3H), 1.32 (s, 6H), 1.36 (s, 3H), 1.38 (s,3H), 2.75-2.87 (m, 1H), 3.82 (d, J=5.0 Hz, 1H), 4.19-4.30 (m, 1H),4.40-4.50 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.61-5.89 (m, 3H),6.02 (d, J=11.2 Hz, 1H), 6.38 (d, J=11.2 Hz, 1H). MS m/z: 424 (M⁺—H₂O),59 (100%). UV λ_(max) nm: 263.

Example 17

[0251] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-20-{4-triethylsilyloxy-4-methyl-(2Z)-pentenyloxy}-20-ethylpregna-5,7,16-triene

[0252]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-ethylpregna-5,7,16-triene(103 mg, 0.180 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-(2Z)-pentene(211 mg, 0.719 mol), sodium hydride (60% in oil, 43 mg, 1.08 mmol),15-crown-5 (40 mg, 0.182 mmol) and tetrahydrofuran (3 ml) were subjectedto reaction using a procedure similar to that of Example 5(1) (refluxunder heating for 1 hour), worked up and purified by columnchromatography (hexane:toluene=1:1) to give the titled compound (141 mg,100%) as a colorless solid. IR(neat): 2956, 2931, 2877, 2856, 1462,1375, 1254, 1169, 1097, 1066, 1041, 1007 cm⁻¹. ¹H NMR δ: 0.05 (s, 3H),0.06 (s, 3H), 0.06 (s, 3H), 0.10 (s, 3H), 0.52-0.66 (m, 6H), 0.87 (s,9H), 0.89 (s, 9H), 1.30 (s, 3H), 1.31 (s, 3H), 2.76-2.87 (m, 1H), 3.71(brs, 1H), 3.98-4.36 (m, 3H), 5.29-5.44 (m, 3H), 5.58-5.66 (m, 2H). MSm/z: 785 (M⁺+1), 73 (100%). UV λ_(max) nm: 271, 282, 294.

[0253] (2) Synthesis of1α,3β-dihydroxy-20-{4-hydroxy-4-methyl-(2Z)-pentenyloxy}-20-methylpregna-5,7,16-triene

[0254]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-{4-triethylsilyloxy-4-methyl-(2Z)-pentenyloxy}-20-methylpregna-5,7,16-triene(140 mg, 0.178 mmol) and a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (5 ml) were subjected to reaction using aprocedure similar to that of Example 5(2) (4 hours), worked up andpurified by column chromatography (ethyl acetate) to give the titledcompound (63 mg, 80%) as a colorless foam. IR(neat): 3377, 2972, 2931,1460, 1369, 1236, 1149, 1039 cm⁻¹. ¹H NMR δ: 0.95 (s, 3H), 0.97 (s, 3H),1.34 (s, 6H), 1.41 (s, 3H), 1.43 (s, 3H), 2.71-2.83 (m, 1H), 3.78 (brs,1H), 3.91 (dd, J=12.9, 5.6 Hz, 1H), 3.99-4.17 (m, 2H), 5.37-5.50 (m,2H), 5.56-5.78 (m, 3H). MS m/z:424(M⁺—H₂O),55(100%). UV λ_(max) nm: 271,282, 294.

[0255] (3) Synthesis of1α,3β-dihydroxy-20-{4-hydroxy-4-methyl-(2Z)-pentenyloxy}-20-methyl-9,10-secopregna-5,7,10(19),16-tetraene

[0256]1α,3β-Dihydroxy-20-{4-hydroxy-4-methyl-(2Z)-pentenyloxy}-20-methylpregna-5,7,16-triene(61 mg, 0.138 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 4min. 45 sec., reflux under heating for 2 hours) and purified bypreparative thin layer chromatography (2 sheets (each 0.5 mm thickness),dichloromethane:ethanol=10:1, developed twice; and 1 sheet (0.5 mmthickness), toluene:ethyl acetate=5:6, developed twice) to give thetitled compound (2.90 mg, 5%) as a colorless glassy substance. IR(neat):3359, 2958, 2925, 2854, 1466, 1363, 1279, 1242, 1146, 1057 cm⁻¹. ¹H NMRδ: 0.85 (s, 3H), 1.26 (s, 6H), 1.34 (s, 3H), 2.74-2.86 (m, 1H),3.89-4.35 (m, 3H), 4.45 (brs, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H),5.30-5.62 (m, 2H), 5.65 (brs, 1H), 6.11 (d, J=11.2 Hz, 1H), 6.38 (d,J=11.2 Hz, 1H). MS m/z: 424 (M⁺—H₂O), 55 (100%). UV λ_(max) nm: 264.

Example 18

[0257] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-20-(4-ethyl-4-triethylsilyloxy-2-hexynyloxy)-20-methylpregna-5,7,16-triene

[0258]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene(100 mg, 0.17 mmol), 1-bromo-4-ethyl-4-triethylsilyloxy-2-hexyne (150mg, 0.47 mmol), sodium hydride (60% in oil, 41 mg, 1.02 mmol),15-crown-5 (37 mg, 0.17 mmol) and tetrahydrofuran (3 ml) were subjectedto reaction using a procedure similar to that of Example 5(1) (at roomtemperature for 17 hours), worked up and purified by preparative thinlayer chromatography (3 sheets (each 1.0 mm thickness),hexane:toluene=1:1) to give the titled compound (52 mg, 37.7%) as ayellow oil. IR(neat): 2954, 2935, 2877, 2856, 1462, 1377, 1329, 1254,1149, 1097, 1082, 1068, 1007 cm⁻¹. ¹H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H),0.11 (s, 3H), 0.67 (q, J=7.6 Hz, 6H), 0.89 (s, 18H), 0.91-1.01 (m, 21H),1.38 (s, 3H), 1.40 (s, 3H), 2.77-2.90 (m, 1H), 3.71 (brs, 1H), 3.97 (s,2H), 4.00-4.14 (m, 1H), 5.35-5.45 (m, 1H), 5.57-5.63 (m, 1H), 5.68 (brs,1H). MS m/z: 782 (M⁺—CH₂CH₃), 73 (100%). UV λ_(max) nm: 271, 282, 294.

[0259] (2) Synthesis of1α,3β-hydroxy-20-(4-ethyl-4-hydroxy-2-hexynyloxy)-20-methylpregna-5,7,16-triene

[0260]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-(4-ethyl-4-triethylsilyloxy-2-hexynyloxy)-20-methylpregna-5,7,16-triene(52 mg, 0.064 mmol) and a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (0.96 ml) were subjected to reaction using aprocedure similar to that of Example 5(2) (2 hours), worked up andpurified by preparative thin layer chromatography (2 sheets (each 0.5 mmthickness), ethyl acetate:dichloromethane=4:1) to give the titledcompound (27 mg, 90.0%) as a colorless foam. IR(neat): 3400, 2970, 2935,2879, 1462, 1369, 1236, 1147, 1041 cm⁻¹. ¹H NMR δ: 0.95 (s, 3H), 0.97(s, 3H), 1.00 (t, J=7.3 Hz, 6H), 1.38 (s, 3H), 1.39 (s, 3H), 2.71-2.85(m, 1H), 3.77 (brs, 1H), 3.97 (s, 2H), 4.00-4.14 (m, 1H), 5.42-5.49 (m,1H), 5.66-5.77 (m, 2H). MS m/z: 450 (M⁺—H₂O), 57 (100%). UV λ_(max) nm:272, 282, 294.

[0261] (3) Synthesis of1α,3β-dihydroxy-20-(4-ethyl-4-hydroxy-2-hexynyloxy)-20-methyl-9,10-secopregna-5,7,10(19),16-tetraene

[0262]1α,3β-Hydroxy-20-(4-ethyl-4-hydroxy-2-hexynyloxy)-20-methylpregna-5,7,16-triene(27 mg, 0.058 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 4min., reflux under heating for 2 hours) and purified by preparative thinlayer chromatography (2 sheets (each 0.5 mm thickness),dichloromethane:ethanol=20:1, developed three times; 2 sheets (each 0.5mm thickness), toluene:ethyl acetate=1:4, developed three times; and 1sheet (0.5 mm thickness), toluene:ethyl acetate=1, developed 1.5 times)to give the titled compound (1.635 mg, 6.1%) as a colorless oil.IR(neat): 3390, 2966, 2925, 2850, 1732, 1462, 1379, 1288, 1144, 1047cm⁻¹. ¹H NMR δ: 0.86 (s, 3H), 1.02 (t, J=7.6 Hz, 6H), 1.38 (s, 6H),2.56-2.66 (m, 1H), 2.76-2.86 (m, 1H), 4.00 (s, 2H), 4.19 -4.31 (m, 1H),4.40-4.50 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.66 (brs, 1H), 6.11(d, J=11.5 Hz, 1H), 6.38 (d, J=11.2 Hz, 1H). MS m/z: 450 (M⁺—H₂O), 57(100%). UV λ_(max) nm: 264.

Example 19

[0263] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-20-{4-ethyl-4-triethylsilyloxy-(2Z)-hexenyloxy}-20-methylpregna-5,7,16-triene

[0264]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene(100 mg, 0.175 mmol), 1-bromo-4-ethyl-4-triethylsilyloxy-(2Z)-hexene(224 mg, 0.697 mmol), sodium hydride (60% in oil, 42 mg, 1.05 mmol),15-crown-5 (38 mg, 0.173 mmol) and tetrahydrofuran (3 ml) were subjectedto reaction using a procedure similar to that of Example 5(1) (refluxunder heating for 17 hours), worked up and purified by columnchromatography (hexane:toluene=2:1) to give the titled compound (102 mg,72%) as a colorless solid. IR(neat): 2956, 2931, 2877, 2856, 1462, 1375,1360, 1254, 1151, 1097, 1080 cm⁻¹. ¹H NMR δ: 0.05 (s, 3H), 0.06 (s, 3H),0.06 (s, 3H), 0.10 (s, 3H), 0.60 (q, J=7.9 Hz, 6H), 0.87 (s, 9H), 0.88(s, 9H), 1.35 (s, 3H), 1.37 (s, 3H), 2.75-2.88 (m, 1H), 3.71 (brs, 1H),3.97-4.36 (m, 3H), 5.03-5.11 (m, 1H), 5.36-5.50 (m, 2H), 5.58-5.67 (m,2H). MS m/z: 813 (M++1), 73 (100%). UV λ_(max) nm: 271, 282, 294.

[0265] (2) Synthesis of20-{4-ethyl-4-hydroxy-(2Z)-hexenyloxy}-1α,3β-dihydroxy-20-methylpregna-5,7,16-triene

[0266]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-{4-ethyl-4-triethylsilyloxy-(2Z)-hexenyloxy}-20-methylpregna-5,7,16-triene(99 mg, 0.122 mmol) and a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (5 ml) were subjected to reaction using aprocedure similar to that of Example 5(2) (3 hours), worked up andpurified by column chromatography (ethyl acetate) to give the titledcompound (52 mg, 91%) as a colorless glassy substance. IR(neat): 3400,2968, 2933, 2877, 1458, 1369, 1151, 1041 cm⁻¹. ¹H NMR δ: 0.85-0.94 (m,6H), 0.95 (s, 3H), 0.97 (s, 3H), 1.39 (s, 3H), 1.41 (s, 3H), 2.70-2.83(m, 1H), 3.87 (dd, J=12.5, 6.3 Hz, 1H),4.00-4.16 (m, 2H), 4.32-5.42 (m,1H), 5.42-5.49 (m, 1H), 5.53-5.79 (m, 3H). MS m/z: 452 (M⁺—H₂O), 326(100%). UV λ_(max) nm: 271, 282, 294.

[0267] (3) Synthesis of20-{4-ethyl-4-hydroxy-(2Z)-hexenyloxy}-1α,3β-dihydroxy-20-methyl-9,10-secopregna-5,7,10(19),16-tetraene

[0268]20-{4-Ethyl-4-hydroxy-(2Z)-hexenyloxy}-1α,3β-dihydroxy-20-methylpregna-5,7,16-triene(51 mg, 0.108 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 4min. 30 sec., reflux under heating for 2 hours) and purified bypreparative thin layer chromatography (2 sheets (each 0.5 mm thickness),dichloromethane:ethanol=10:1, developed twice; and 1 sheet (0.5 mmthickness), toluene:ethyl acetate=5:6, developed twice) to give thetitled compound (1.69 mg, 3%) as a colorless glassy substance. IR(neat):2966, 2929, 2877, 2850, 1462, 1442, 1377, 1145, 1050 cm⁻¹. ¹H NMR δ:0.85 (s, 3H), 0.86-0.94 (m, 6H), 1.39 (s, 3H), 1.39 (s, 3H), 2.74-2.85(m, 1H), 3.86-4.10 (m, 2H), 4.19-4.29 (br, 1H), 4.40-4.49 (br, 1H), 5.01(brs, 1H), 5.32-5.72 (m, 4H), 6.11 (d, J=11.2 Hz, 1H), 6.38 (d, J=11.2Hz, 1H). MS m/z: 470 (M⁺), 57 (100%). UV λ_(max) nm: 263.

Example 20

[0269] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-20-{4-ethyl-4-triethylsilyloxy-(2E)-hexenyloxy}-20-methylpregna-5,7,16-triene

[0270]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene(400 mg, 0.698 mmol), 1-bromo-4-ethyl-4-triethylsilyloxy-(2E)-hexene(0.897 g, 2.79 mmol), sodium hydride (60% in oil, 0.168 g, 4.188 mmol),15-crown-5 (0.14 ml, 0.698 mmol) and tetrahydrofuran (12 ml) weresubjected to reaction using a procedure similar to that of Example 5(1)(3 hours), worked up and purified by column chromatography(hexane:toluene=2:1) to give the titled compound (0.35 g, 62%) as ayellow foam. ¹H NMR δ: 0.05 (s, 3H), 0.07 (s, 3H), 0.10 (s, 3H), 0.11(s, 3H), 0.57 (q, J=7.3 Hz, 6H), 0.81 (t, J=7.6 Hz, 6H), 0.88 (s, 9H),0.89 (s, 9H), 1.36 (s, 3H), 1.37 (s, 3H), 2.84 (brs, 1H), 3.71 (brs,1H), 3.77-3.84 (m, 2H), 4.05 (brs, 1H), 5.40 (brs, 1H), 5.57-5.66 (m,4H).

[0271] (2) Synthesis of20-{4-ethyl-4-hydroxy-(2E)-hexenyloxy}-1α,3β-dihydroxy-20-methylpregna-5,7,16-triene

[0272]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-{4-ethyl-4-triethylsilyloxy-(2E)-hexenyloxy}-20-methylpregna-5,7,16-triene(350 mg, 0.430 mmol) and a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (15 ml) were subjected to reaction using aprocedure similar to that of Example 5(2) (3 hours), worked up andpurified by column chromatography (ethyl acetate) to give the titledcompound (200 mg, 100%) as a yellow foam. ¹H NMR δ: 0.86(t, J=5.6 Hz,6H), 0.95 (s, 3H), 0.98 (s, 3H), 1.37 (s, 3H), 1.39 (s, 3H), 3.73-3.86(m, 3H), 4.10 (m, 1H), 5.46 (m, 1 H), 5.61-5.78 (m, 4H).

[0273] (3) Synthesis of20-{4-ethyl-4-hydroxy-(2E)-hexenyloxy}-1α,3β-dihydroxy-20-methyl-9,10-secopregna-5,7,10(19),16-tetraene

[0274]20-{4-Ethyl-4-hydroxy-(2E)-hexenyloxy}-1α,3β-dihydroxy-20-methylpregna-5,7,16-triene(0.125 g, 0.266 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 6min., reflux under heating for 2 hours) and purified by preparative thinlayer chromatography (1 sheet (0.5 mm thickness),dichloromethane:ethanol=10:1, developed once; and 1 sheet (0.5 mmthickness), ethyl acetate:toluene=1:1, developed twice) to give thetitled compound (14.4 mg, 12%) as a colorless oil. IR(neat): 3566, 2970,2933, 1489, 1377, 1146, 1053cm⁻¹. ¹H NMR δ: 0.85(t, J=10.8 Hz, 6H), 0.86(s, 3H), 1.36 (s, 3H), 1.37 (s, 3H), 3.84-3.85 (m, 2H), 4.24 (brs, 1H),4.43 (brs, 1H), 5.01 (s, 1H), 5.34 (s, 1H), 5.63-5.71 (m, 3H), 6.11 (d,J=11.5 Hz, 1H), 6.38 (d, J=11.5 Hz, 1H). MS m/z: 452 (M⁺—H₂O), 133(100%). UV λ_(max) nm: 264.

Example 21

[0275] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-20-(2-hydroxy-2-methylpropoxy)-20-methylpregna-5,7,16-triene

[0276] A solution of1α,3β-bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene(49.2 mg, 0.0859 mmol), potassium hydride (35% in oil, 0.1 ml, 0.873mmol) and dibenzo-18-crown-6 (30 mg, 0.0832 mmol) in toluene (0.2 ml)was stirred at room temperature for 3 min., 1,2-epoxy-2-methylpropane(60 mg, 0.832 mmol) was added and stirred at external temperature of 45°C. for 1.5 hours. The reaction solution was cooled with ice and waterwas added. The mixture was diluted with ethyl acetate, washed withsaturated brine and the organic layer was dried over anhydrous magnesiumsulfate. After evaporating under reduced pressure to remove the solvent,the thus obtained residue was purified by preparative thin layerchromatography (2 sheets (each 0.5 mm thickness), hexane:ethylacetate=15:1, developed twice) to give the titled compound (10.4 mg,19%) and1α,3β-bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene(18.6 mg, 38%), each as a colorless oil. IR(neat): 3400, 2932, 2896,2856, 1462, 1360, 1254, 1078, 836, 1774 cm⁻¹. ¹H NMR δ: 0.05 (s, 3H),0.06 (s, 6H) 0.11 (s, 3H), 0.88 (s, 18H), 0.94 (s, 3H), 0.95 (s, 3H),1.18 (s, 3H), 1.19 (s, 3H), 1.34 (s, 3H), 1.37 (s, 3H), 1.87-1.99 (m,1H), 2.78-2.89 (m, 1H), 3.07 (d, J=8.5 Hz, 1H), 3.10 (d, J=8.5 Hz, 1H),3.72 (brs, 1H), 3.98-4.12 (m, 1H), 5.36-5.44 (m, 1H), 5.57-5.66 (m, 2H).MS m/z: 644 (M⁺), 73 (100%). UV λ_(max) nm: 271, 282, 294.

[0277] (2) Synthesis of1α,3β-dihydroxy-20-(2-hydroxy-2-methylpropoxy)-20-methylpregna-5,7,16-triene

[0278]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-(2-hydroxy-2-methylpropoxy)-20-methylpregna-5,7,16-triene(35.6 mg, 0.0552 mmol), a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (0.35 ml) and tetrahydrofuran (0.5 ml) weresubjected to reaction using a procedure similar to that of Example 5(2)(reflux under heating for 12 hours), worked up and the thus obtainedresidue was purified by preparative thin layer chromatography (1 sheet(0.5 mm thickness), dichloromethane:ethanol=15:1, developed three times)to give the titled compound (18.1 mg, 79%) as a colorless oil. IR(neat):3396, 2972, 2932, 1462, 1376, 1238, 1152, 1080 cm⁻¹. ¹H NMR δ: 0.96 (s,3H), 0.98 (s, 6H), 1.19 (s, 6H), 1.34 (s, 3H), 1.38 (s, 3H), 2.49-2.61(m,1H), 2.70-2.84 (m, 1H), 3.07 (d, J=8.8 Hz, 1H), 3.11 (d, J=8.8 Hz,1H), 3.77 (brs, 1H), 4.00-4.18 (m, 1H), 5.41-5.50 (m, 1H), 5.64 (brs,1H) 5.71-5.79 (m, 1H). MS m/z: 416 (M⁺), 59 (100%). UV λ_(max) nm: 271,282, 294.

[0279] (3) Synthesis of1α,3β-dihydroxy-20-(2-hydroxy-2-methylpropoxy)-20-methyl-9,10-secopregna-5,7,10(19),16-tetraene

[0280]1α,3β-Dihydroxy-20-(2-hydroxy-2-methylpropoxy)-20-methylpregna-5,7,16-triene(24.3 mg, 0.0583 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 2.5min., reflux under heating for 2 hours) and purified by preparative thinlayer chromatography (1 sheet (0.5 mm thickness),dichloromethane:ethanol=15:1, developed three times; 1 sheet (0.25 mmthickness), hexane:ethyl acetate:ethanol=10:5:1, developed three times;and 1 sheet (0.25 mm thickness), dichloromethane:ethyl acetate=3:1,developed three times) to give the titled compound (1.199 mg, 5%) as acolorless foam. IR(neat): 3356, 2968, 2932, 1434, 1360, 1240, 1150,1074, 914 cm⁻¹. ¹H NMR δ:0.85 (s, 3H), 1.20 (s, 6H), 1.34 (s, 3H), 1.36(s, 3H), 2.56-2.68 (m, 1H), 2.75-2.88 (m, 1H), 3.10 (s, 2H), 4.18-4.30(m, 1H), 4.39-4.50 (m, 1H), 5.01 (s, 1H), 5.34 (s, 1H), 5.61 (s, 1H),6.11 (d, J=11.2 Hz, 1H), 6.50 (d, J=11.2 Hz, 1H). MS m/z: 326(M⁺—HOCH₂C(CH₃)₂OH), 59 (100%). UVλ_(max) nm: 264.

Example 22

[0281] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-20-(2-ethyl-2-hydroxybutoxy)-20-methylpregna-5,7,16-triene

[0282]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene(261.4 mg, 0.456 mmol), potassium hydride (35% in oil, 0.53 ml, 4.625mmol), dibenzo-18-crown-6 (165 mg, 0.458 mmol), toluene (0.75 ml) and1,2-epoxy-2-ethylbutane (450 mg, 4.493 mmol) were subjected to reactionusing a procedure similar to that of Example 21(1) (at externaltemperature of 95° C. for 2 hours and 10 min.), worked up and the thusobtained residue was purified by column chromatography (hexane:ethylacetate=10:1) and preparative thin layer chromatography (1 sheet (0.5 mmthickness), hexane:ethyl acetate=20:1, developed twice) to give thetitled compound (32.0 mg, 10%) and1α,3β-bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene(138.5 mg, 53%), each as a colorless oil. IR(neat): 3336, 2932, 2888,1462, 1254, 1084, 836, 774 cm⁻¹. ¹H NMR δ: 0.05 (s, 3H), 0.06 (s, 6H)0.10 (s, 3H), 0.85 (t, J=7.7 Hz, 6H), 0.88 (s, 9H), 0.89 (s, 9H), 0.92(s, 3H), 0.94 (s, 3H), 1.34 (s, 3H), 1.36 (s, 3H), 1.50 (q, J=7.7 Hz,4H), 2.78-2.90 (m, 1H), 3.11 (s, 2H), 3.70 (brs, 1H), 3.95-4.12 (m, 1H),5.35-5.44 (m, 1H), 5.57-5.65 (m, 1H), 5.63 (brs, 1H). MS m/z: 554(M⁺—HOCH₂C(CH₂CH₃)₂OH), 73 (100%). UV λ_(max) nm: 271, 282, 293.

[0283] (2) Synthesis of20-(2-ethyl-2-hydroxybutoxy)-1α,3β-dihydroxy-20-methylpregna-5,7,16-triene

[0284]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-(2-ethyl-2-hydroxybutoxy)-20-methylpregna-5,7,16-triene(32.0 mg, 0.0475 mmol), a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (0.3 ml, 0.3 mmol) and tetrahydrofuran (0.5 ml)were subjected to reaction using a procedure similar to that of Example5(2) (reflux under heating for 16 hours), worked up and the thusobtained residue was purified by preparative thin layer chromatography(1 sheet (0.5 mm thickness), hexane:ethyl acetate:ethanol=10:5:1,developed twice) to give the titled compound (19.8 mg, 94%) as acolorless oil. IR(neat): 3400, 2964, 2932, 1460, 1376, 1274, 1136, 1072,1040, 736 cm⁻¹. ¹H NMR δ: 0.84 (t, J=7.3 Hz, 3H), 0.86 (t, J=7.3 Hz,3H), 0.95 (s, 3H), 0.96 (s, 3H), 1.34 (s, 3H), 1.37 (s, 3H), 1.48 (q,J=7.3 Hz, 4H), 2.46 -2.62 (m, 1H), 2.70-2.88 (m, 1H), 3.09 (d, J=8.7 Hz,1H), 3.14 (d, J=8.7 Hz, 1H), 3.76 (brs, 1H), 3.98-4.14 (m, 3H),5.40-5.53 (m, 1H), 5.64 (brs, 1H), 5.70-5.82 (m, 1H). MS m/z: 326(M⁺⁻HOCH₂C(CH₂CH₃)₂OH), 87 (100%). UV λ_(max) nm: 271, 282, 294.

[0285] (3) Synthesis of20-(2-ethyl-2-hydroxypropoxy)-1α,3β-dihydroxy-20-methyl-9,10-secopregna-5,7,10(19),16-tetraene20-(2-Ethyl-2-hydroxybutoxy)-1α,3β-dihydroxy-20-methylpregna-5,7,16-triene(19.8 mg, 0.0445 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 2min. 15 sec., reflux under heating for 2 hours) and purified bypreparative thin layer chromatography (1 sheet (0.25 mm thickness),dichloromethane:ethanol=15:1, developed twice; and 1 sheet (0.25 mmthickness), dichloromethane:ethyl acetate=3:1, developed three times) togive the titled compound (1.150 mg, 6%) as a colorless foam. IR(neat):3368, 2928, 1460, 1376, 1244, 1056, 912 cm⁻¹. ¹H NMR δ: 0.84 (s, 3H),0.82-0.92 (m, 6H), 1.33 (s, 3H), 1.35 (s, 3H), 1.44-1.63 (m, 4H),2.55-2.66 (m, 1H), 2.74-2.85 (m, 1H), 3.12 (s, 2H), 4.19-4.30 (m, 1H),4.39-4.59 (m, 1H), 5.01 (s, H), 5.33 (s, 1H), 5.59 (s, 1H), 6.10 (d,J=11.5 Hz, 1H), 6.38 (d, J=11.5 Hz, 1H). MS m/z: 326(M⁺—HOCH₂C(CH₂CH₃)₂OH), 87 (100%). UV λ_(max) nm: 264.

Example 23

[0286] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(2,3-epoxy-3-methylbutoxymethyl)androsta-5,7,16-triene

[0287] A solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene(51.6 mg, 0.0947 mmol), sodium hydride (95%, 21.1 mg, 0.879 mmol) and1-bromo-2,3-epoxy-3-methylbutane (91.2 mg, 0.553 mmol) intetrahydrofuran (1 ml) was stirred at room temperature for 20 min. andrefluxed under heating for 20 min. The reaction solution was dilutedwith ethyl acetate and washed with water and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, evaporatedunder reduced pressure to remove the solvent, and the thus obtainedresidue was purified by preparative thin layer chromatography (1 sheet(0.5 mm thickness), hexane:ethyl acetate=10:1, developed twice) to givethe titled compound (48.3 mg, 81%) as a pale yellow oil. IR(neat): 3036,2928, 2856, 1460, 1376, 1252, 1068, 832, 774 cm⁻¹. ¹H NMR δ: 0.05 (s,3H), 0.06 (s, 6H), 0.11 (s, 3H), 0.84 (s, 3H), 0.88 (s, 18H), 0.94 (s,3H), 1,29 (s, 3H), 1.34 (s, 3H), 2.81-2.91 (m, 1H), 2.97 (t, J=5.4 Hz,1H), 3.45-3.57 (m, 1H), 3.63 (dd, J=5.0, 11.1 Hz, 1H), 3.70 (brs, 1H),3.96-4.20 (m, 3H), 5.35-5.43 (m, 1H), 5.60 (d, J=5.4 Hz, 1H), 5.68 (brs,1H). UV λ_(max) nm: 269, 281, 293.

[0288] (2) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(3-hydroxy-3-methylbutoxymethyl)androsta-5,7,16-triene

[0289] At room temperature, a solution of 1.0M L-SELECTRIDE intetrahydrofuran (0.25 ml, 0.25 mmol) was added to a solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(2,3-epoxy-3-methylbutoxymethyl)androsta-5,7,16-triene(48.3 mg, 0.0768 mmol) in tetrahydrofuran (2 ml) and stirred at the sametemperature for 1 hour. To the solution, was further added a solution of1.0M L-SELECTRIDE in tetrahydrofuran (0.2 ml, 0.2 mmol), followed bystirring at the same temperature for 1 hour. After cooling the reactionsolution with ice, a 3N aqueous sodium hydroxide solution and thenhydrogen peroxide solution were added. Immediately after the addition,the mixture was diluted with ethyl acetate and washed with water andsaturated brine. The organic layer was dried over anhydrous magnesiumsulfate and evaporated to remove the solvent under reduced pressure; thethus obtained residue was purified by preparative thin layerchromatography (1 sheet (0.5 mm thickness), hexane:ethyl acetate=10:1,developed twice) to give the titled compound (42.0 mg, 87%) as acolorless oil. IR(neat): 3500, 3036, 2952, 2856, 1462, 1372, 1254, 1096,838, 772 cm⁻¹. ¹H NMR δ: 0.05 (s, 3H), 0.06 (s, 6H), 0.10 (s, 3H), 0.83(s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 0.94 (s, 3H), 1.25 (s, 6H), 1.77(t, J=5.9 Hz, 2H), 2.79-2.91 (m, 1H), 3.60-3.75 (m, 3H), 3.94-4.12 (m,3H), 5.35-5.44 (m, 1H), 5.60 (d, J=5.4 Hz, 1H), 5.63 (brs, 1H). MS m/z:630 (M⁺), 73 (100%). UV λ_(max) nm: 269, 281, 293.

[0290] (3) Synthesis of1α,3β-dihydroxy-17-(3-hydroxy-3-methylbutoxymethyl)androsta-5,7,16-triene

[0291]1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(3-hydroxy-3-methylbutoxymethyl)androsta-5,7,16-triene(40.0 mg, 0.0634 mmol) and a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (0.4 ml, 0.4 mmol) were subjected to reactionusing a procedure similar to that of Example 5(2) (reflux under heatingfor 1 hour), worked up and the thus obtained residue was purified bypreparative thin layer chromatography (dichloromethane:ethanol=10:1,developed once) to give the titled compound (20.9 mg, 82%) as acolorless oil. IR(neat): 3392, 2968, 2932, 1460, 1370, 1154, 1056, 732cm⁻¹. ¹H NMR δ: 0.83 (s, 3H), 0.96 (s, 3H), 1.24 (s, 6H), 2.46-2.59 (m,1H), 2.73-2.86 (m, ₁H), 3.60-3.73 (m, 2H), 3.76 (brs, 1H), 3.99 (d,J=12.9 Hz, 1H), 4.06 (d, J=12.9 Hz, 1H), 5.39-5.48 (m, 1H), 5.64 (s,1H), 5.67-5.76 (m, 1H). MS m/z: 401 (M⁺−1), 298 (100%), UV λ_(max) nm:270, 282, 293.

[0292] (4) Synthesis of1α,3β-dihydroxy-17-(3-hydroxy-3-methylbutoxymethyl)-9,10-secoandrosta-5,7,10(19),16-tetraene

[0293]1α,3β-Dihydroxy-17-(3-hydroxy-3-methylbutoxymethyl)androsta-5,7,16-triene(20.0 mg, 0.0497 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 2min. 15 sec., reflux under heating for 1.5 hours) and purified bypreparative thin layer chromatography (1 sheet (0.25 mm thickness),dichloromethane:ethanol=10:1, developed twice; and 1 sheet (0.25 mmthickness), hexane:ethyl acetate:ethanol=10:5:1, developed twice) togive the titled compound (2.135 mg, 11%) as a colorless oil. IR(neat):3376, 2928, 1452, 1368, 1056, 960, 800, 728 cm⁻¹. ¹H NMR δ: 0.73 (s,3H), 1.25 (s, 6H), 1.78 (t, J=5.9 Hz, 2H), 2.53-2.68 (m, 1H), 2.74-2.87(m, 1H), 3.35 (s, 1H), 3.59-3.77 (m, 2H), 3.97 (d, J=13.7 Hz, 1H), 4.04(d, J=13.7 Hz, 1H), 4.17-4.30 (m, 1H), 4.38-4.51 (m, 1H), 5.01 (s, 1H),5.33 (s, 1H), 5.60 (s, 1H), 6.09 (d, J=11.2 Hz, 1H), 6.37 (d, J=11.2 Hz,1H). MS m/z: 298 (M⁺—HOCH₂CH₂C(CH₃)₂OH), 59 (100%). UV λ_(max) nm: 264.

Example 24

[0294] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-20-(3-hydroxy-3-methylbutoxy)-20-methylpregna-5,7,16-triene

[0295] A solution of1α,3β-bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene(67.7 mg, 0.118 mmol), sodium hydride (60% in oil, 40.0 mg, 1.00 mmol)and 1-bromo-2,3-epoxy-3-methylbutane (100 mg, 0.606 mmol) intetrahydrofuran (1 ml) was refluxed under heating for 1.5 hours. To thethus obtained reaction solution, was added 1.0ML-SELECTRIDE/tetrahydrofuran solution (1.2 ml, 1.2 mmol) at roomtemperature, followed by stirring at the same temperature for 12 hours.After cooling the reaction solution with ice, a 3N aqueous sodiumhydroxide solution and then hydrogen peroxide solution were added to thereaction solution. Immediately after the addition, the mixture wasdiluted with ethyl acetate and washed with water and saturated brine.The organic layer was dried over anhydrous magnesium sulfate andevaporated to remove the solvent under reduced pressure; the thusobtained residue was purified by preparative thin layer chromatography(2 sheets (each 0.5 mm thickness), hexane:ethyl acetate=15:1, developedonce) to give the titled compound (72.5 mg, 93%) as a colorless oil.IR(neat): 3528, 2952, 2932, 2888, 2856, 1462, 1374, 1360, 1254, 1150,1080, 968, 834, 774 cm⁻¹. ¹H NMR δ: 0.05 (s, 3H), 0.06 (s, 3H), 0.07 (s,3H),0.10 (s, 3H), 0.88 (s, 21H), 0.93 (s, 3H), 1.21 (s, 3H), 1.22 (s,3H), 1.37 (s, 6H), 2.75-2.89 (m, 1H), 3.37-3.49 (m, 1H), 3.49-3.61 (s,1H), 3.70 (brs, 1H), 3.81 (brs, 1H), 3.95-4.13 (m, 1H), 5.35-5.44 (m,1H), 5.60 (d, J=5.4 Hz, 1H), 5.66 (brs, 1H). MS m/z: 658 (M⁺), 73(100%). UV λ_(max) nm: 271, 282, 294.

[0296] (2) Synthesis of1α,3β-hydroxy-20-(3-hydroxy-3-methylbutoxy)-20-methylpregna-5,7,16-triene

[0297]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-(3-hydroxy-3-methylbutoxy)-20-methylpregna-5,7,16-triene(98.0 mg, 0.149 mmol), a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (1.0 ml, 1.0 mmol) and tetrahydrofuran (1 ml)were subjected to reaction using a procedure similar to that of Example5(2) (reflux under heating for 4.5 hours), worked up and the thusobtained residue was purified by preparative thin layer chromatography(1 sheet (0.5 mm thickness), dichloromethane:ethanol=15:1, developedtwice) to give the titled compound (52.9 mg, 83%) as a colorless oil.IR(neat): 3408, 2968, 2932, 1462, 1378, 1148, 1056, 1040, 910, 732 cm⁻¹.¹H NMR δ: 0.93 (s, 3H), 0.96 (s, 3H), 1.21 (s, 3H), 1.22 (s, 3H), 1.37(s, 3H), 1.38 (s, 3H), 2.46-2.59 (m, 1H), 2.71-2.84 (m, 1H), 3.39-3.50(m, 1H), 3.50-3.62 (m, 1H), 3.77 (brs, 1H), 3.98-4.16 (m, 2H), 5.38-5.50(m, 1H), 5.66 (s, 1H), 5.69-5.76 (m, 1H). MS m/z: 371 (M⁺—C(CH₃)₂OH),326 (100%). UV λ_(max) nm: 271, 282, 294.

[0298] (3) Synthesis of1α,3β-dihydroxy-20-(3-hydroxy-3-methylbutoxy)-20-methyl-9,10-secopregna-5,7,10(19),16-tetraene

[0299]1α,3β-Hydroxy-20-(3-hydroxy-3-methylbutoxy)-20-methylpregna-5,7,16-triene(52 mg, 0.121 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 4.5min., reflux under heating for 2 hours) and purified by preparative thinlayer chromatography (1 sheet (0.5 mm thickness),dichloromethane:ethanol=20:1, developed twice, anddichloromethane:ethanol=15:1, developed twice; 1 sheet (0.25 mmthickness), hexane:ethyl acetate:ethanol=10:5:1, developed three times;and 1 sheet (0.25 mm thickness), dichloromethane:ethyl acetate=3:1,developed twice, dichloromethane:ethyl acetate=2:1, developed once anddichloromethane:ethyl acetate=1:1, developed once) to give the titledcompound (2.903 mg, 6%) as a colorless foam. IR(neat): 3392, 2968, 2932,1438, 1364, 1146, 1060, 908, 732 cm⁻¹. ¹H NMR δ: 0.84 (s, 3H), 1.23 (s,3H), 1.24 (s, 3H), 1.36 (s, 3H), 1.38 (s, 3H), 2.53-2.68 (m, 1H),2.74-2.88 (m, 1H), 3.40-3.53 (m, 2H), 3.53-3.64 (m, 1H), 4.16-4.30 (m,1H), 4.38-4.51 (m, 1H), 5.01 (s, 1H), 5.34 (s, 1H), 5.64 (s, 1H), 6.10(d, J=11.3 Hz, 1H), 6.38 (d, J=11.3 Hz, 1H). MS m/z: 326(M⁺—HOCH₂CH₂C(CH₃)₂OH), 59 (100%). UV λ_(max) nm: 263.

Example 25

[0300] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(N,N-dimethylaminocarbonylethoxymethyl)androsta-5,7,16-triene

[0301] To a solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17-hydroxymethylandrosta-5,7,16-triene(951 mg, 1.75 mmol) in tetrahydrofuran (17.5 ml), was added sodiumhydride (60% in oil, 105 mg, 2.62 mmol), followed by stirring undernitrogen stream at room temperature for 30 min. After addingN,N-dimethylacrylamide (540 mg, 5.44 mmol), the solution was stirred at5° C. for 14 hours, poured into a saturated aqueous ammonium chloridesolution, extracted with ethyl acetate (3 times) and washed withsaturated brine and water. The organic layer was dried over anhydrousmagnesium sulfate and evaporated to remove the solvent under reducedpressure; the thus obtained residue was purified by columnchromatography (hexane:ethyl acetate 2:1) to give the titled compound(1.05 g, 92.7%) as a yellow oil. IR(neat): 2954, 2929, 2895, 2856, 1653,1462, 1398, 1371, 1254, 1097, 1074 cm⁻¹. ¹H NMR δ: 0.05 (s, 3H), 0.06(s, 6H), 0.11 (s, 3H), 0.82(s, 3H), 0.877 (s, 9H), 0.881 (s, 9H), 0.94(s, 3H), 2.62 (t, J=6.6 Hz, 2H), 2.80-2.90 (m, 1H), 2.94 (s, 3H), 3.02(s, 3H), 3.70 (brs, 1H), 3.76 (t, J=6.6H z, 2H), 3.96-4.12 (m, 4H),5.34-5.42 (m, 1H), 5.55-5.67 (m, 2H). MS m/z: 644 (M⁺−1), 73 (100%). UVλ_(max) nm: 271, 281, 293.

[0302] (2) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(3-ethyl-3-hydroxypentyloxymethyl)androsta-5,7,16-triene

[0303] Tetrahydrofuran (11 ml) was mixed with anhydrous cerous (III)chloride (2.33 g, 9.46 mmol), stirred under nitrogen stream at roomtemperature for 30 min., cooled with ice, mixed with ethylmagnesiumbromide (0.96 mol/l, 9.0 ml, 8.6 mmol) and stirred for 30 min. Thereaction solution was mixed with a solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(N,N-dimethylaminocarbonylethoxymethyl)androsta-5,7,16-triene(553 mg, 0.86 mmol) in tetrahydrofuran (11 ml) at 0° C., followed bystirring for 1 hour at the same temperature. The reaction solution waspoured into a saturated aqueous ammonium chloride solution, extractedwith ethyl acetate (3 times), washed with saturated brine and water,dried over anhydrous magnesium sulfate and evaporated under reducedpressure to remove solvent, giving a reaction mixture containing aketone body. The thus obtained mixture was again subjected to the samereaction and worked up; the thus obtained residue was purified by columnchromatography (hexane:ethyl acetate=5:1) to give the titled compound(317 mg, 56.0%) as a yellow oil. IR(neat): 3681, 2956, 2929, 2883, 2856,1471, 1462, 1371, 1362, 1255, 1097, 1070 cm⁻¹. ¹H NMR δ: 0.05 (s, 3H),0.06 (s, 6H), 0.11 (s, 3H), 0.78-0.96 (m, 30H), 2.79-2.92 (m, 1H),3.56-3.74 (m, 1H), 3.93-4.11 (m, 3H), 5.33-5.43 (m, 1H), 5.55-5.66 (m,2H). MS m/z: 658 (M⁺−1), 73 (100%). UV λ_(max) nm: 271, 281, 294.

[0304] (3) Synthesis of1α,3β-dihydroxy-17-(3-ethyl-3-hydroxypentyloxymethyl)androsta-5,7,16-triene

[0305]α,3β-Bis(tert-butyldimethylsilyloxy)-17-(3-ethyl-3-hydroxypentyloxymethyl)androsta-5,7,16-triene(377 mg, 0.57 mmol), a 1M tetra-n-butylammonium fluoride tetrahydrofuransolution (5.7 ml) and tetrahydrofuran (2.2 ml) were subjected toreaction using a procedure similar to that of Example 5(2) (2 hours),worked up and purified by preparative thin layer chromatography (4sheets (each 1.0 mm thickness), ethyl acetate:dichloromethane=4:1) togive the titled compound (213 mg, 86.9%) as a brown foam. IR(neat):3400, 2964, 2937, 2879, 1460, 1371, 1271, 1142, 1061 cm⁻¹. ¹H NMR δ:0.81-0.91 (m, 9H), 0.98 (s, 3H), 2.48-2.62 (m, 1H), 2.72-2.87 (m, 1H),3.60-3.70 (m, 2H), 3.78 (brs, 1H), 3.95-4.15 (m, 3H), 5.41-5.49 (m, 1H),5.64 (brs, 1H), 5.71-5.77 (m, 1H). MS m/z: 298 (M⁺—HO(CH₂)₂CEt₂OH), 57(100%). UV λ_(max) nm: 271, 281, 294.

[0306] (4) Synthesis of1α,3β-dihydroxy-17-(3-ethyl-3-hydroxypentyloxymethyl)-9,10-secoandrosta-5,7,10(19),16-tetraene

[0307]1α,3β-Dihydroxy-17-(3-ethyl-3-hydroxypentyloxymethyl)androsta-5,7,16-triene(213 mg, 4.88 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 11min. 15 sec., reflux under heating for 2 hours) and purified bypreparative thin layer chromatography (5 sheets (each 0.5 mm thickness),dichloromethane:ethanol=20:1, developed three times; and 2 sheets (each0.5 mm thickness), hexane:ethyl acetate:ethanol=3:7:0.5, developed threetimes) to give the titled compound (24.798 mg, 11.6%) as a colorlessoil. IR(neat): 3400, 3035, 2964, 2879, 2850, 1460, 1450, 1369, 1092,1061 cm⁻¹. ¹H NMR δ: 0.72 (s, 3H), 0.86 (t, J=7.6 Hz, 6H), 2.53-2.64 (m,1H), 2.74-2.85 (m, 1H), 3.58-3.67 (m, 2H), 3.92-4.06 (m, 2H), 4.15-4.28(m, 1H), 4.37-4.48 (m, 1H), 5.00 (brs, 1H), 5.33 (brs, 1H), 5.59 (brs,1H), 6.09 (d, J=11.2 Hz, 1H), 6.35 (d, J=10.9 Hz, 1H). MS m/z: 298(M⁺—HO(CH₂)₂CEt₂OH), 134 (100%). UV λ_(max) nm: 265.

Example 26

[0308] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-20-(N,N-dimethylaminocarbonylethoxy)-20-methylpregna-5,7,16-triene

[0309]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene(200 mg, 0.36 mmol), N,N-dimethylacrylamide (107 mg, 1.08 mmol), sodiumhydride (60% in oil, 23 mg, 0.56 mmol) and tetrahydrofuran (4 ml) weresubjected to reaction using a procedure similar to that of Example 25(1)(17 hours at room temperature), worked up and purified by preparativethin layer chromatography (4 sheets (each 1.0 mm thickness), ethylacetate) to give the titled compound (114 mg, 47.1%) as white powder.IR(neat): 2954, 2929, 2884, 2856, 1651, 1462, 1414, 1252, 1151, 1084,1063 cm⁻¹. ¹H NMR δ: 0.01-0.08 (m, 9H), 0.10 (s, 3H), 0.85-0.91 (m, 2H),0.87 (s, 9H), 0.88 (s, 9H), 0.93 (s, 6H), 1.35 (s, 6H), 2.46-2.63 (m,2H), 2.76-2.88 (m, 1H), 2.92 (s, 3H), 3.00 (s, 3H), 3.46-3.68 (m, 2H),3.70 (brs, 1H), 3.95-4.11 (m, 1H), 5.34-5.43 (m, 1H), 5.56-5.68 (m, 2H).MS m/z: 554 (M⁺−1-HO(CH₂)₂CONMe₂), 73 (100%). UV λ_(max) nm: 271, 282,294.

[0310] (2) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-20-(3-ethyl-3-hydroxypentyloxy)-20-methylpregna-5,7,16-triene

[0311]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-(N,N-dimethylaminocarbonylethoxy)-20-methylpregna-5,7,16-triene(133 mg, 0.20 mmol), anhydrous cerous (III) chloride (2.17 g, 8.8 mmol),ethylmagnesium bromide (8.3 ml, 8.0 mmol) and tetrahydrofuran (10 ml)were subjected to reaction using a procedure similar to that of Example25(2) (at 0° C. for 1 hour), worked up and purified by preparative thinlayer chromatography (2 sheets (each 1.0 mm thickness), hexane:ethylacetate=5:1) to give the titled compound (70.7 mg, 51.7%) as a colorlessoil. IR(neat): 3509, 2956, 2929, 2883, 2856, 1462, 1375, 1254, 1149,1097, 1066 cm⁻¹. ¹H NMR δ: 0.05 (s, 3H), 0.06 (s, 3H), 0.07 (s, 3H),0.11 (s, 3H), 0.79-0.98 (m, 30H), 1.36 (s, 6H), 2.77-2.89 (m, 1H),3.35-3.46 (m, 1H), 3.47-3.56 (m, 1H), 3.71 (brs, 1H), 3.96-4.12 (m, 1H),5.37-5.43 (m, 1H), 5.57-5.63 (m, 1H), 5.66 (brs, 1H). MS m/z: 555(M⁺—HOCH₂CH₂CEt₂OH), 73 (100%). UV λ_(max) nm: 271, 282, 294.

[0312] (3) Synthesis of1α,3β-dihydroxy-20-(3-ethyl-3-hydroxypentyloxy)-20-methylpregna-5,7,16-triene

[0313]1α,3β-Bis(tert-butyldimethylsilyloxy)-20-(3-ethyl-3-hydroxypentyloxy)-20-methylpregna-5,7,16-triene(85 mg, 0.12 mmol), a 1M tetra-n-butylammonium fluoride tetrahydrofuransolution (1.2 ml) and tetrahydrofuran (4.6 ml) were subjected toreaction using a procedure similar to that of Example 5(2) (3 hours),worked up and purified by preparative thin layer chromatography (3sheets (each 0.5 mm thickness), ethyl acetate:dichloromethane=4:1) togive the titled compound (55 mg, 100%) as a colorless oil. IR(neat):3399, 2968, 2935, 2879, 1653, 1458, 1377, 1149, 1061 cm⁻¹. ¹H NMR δ:0.78-0.89 (m, 6H), 0.93 (s, 3H), 0.95 (s, 3H), 1.36 (s, 3H), 1.37 (s,3H), 2.71-2.84 (m, 1H), 3.36-3.58 (m, 2H), 3.76 (brs, 1H), 3.97-4.14 (m,1H), 5.40-5.47 (m, 1H), 5.65 (brs, 1H), 5.68-5.75 (m, 1H). MS m/z: 344(M⁺—CH₂CH₂CEt₂OH), 326 (100%). UV λ_(max) nm: 271, 282, 294.

[0314] (4) Synthesis of1α,3β-dihydroxy-20-(3-ethyl-3-hydroxypentyloxy)-20-methyl-9,10-secopregna-5,7,10(19),16-tetraene

[0315]1α,3β-Dihydroxy-20-(3-ethyl-3-hydroxypentyloxy)-20-methylpregna-5,7,16-triene(55 mg, 0.12 mmol) and ethanol (200 ml) were subjected to reaction usinga procedure similar to that of Example 5(3) (irradiation for 4 min. 45sec., reflux under heating for 2 hours) and purified by preparative thinlayer chromatography (2 sheets (each 0.5 mm thickness),dichloromethane:ethanol=20:1, developed three times; 2 sheets (each 0.5mm thickness), toluene:ethyl acetate=1:4, developed three times; and 2sheets (each 0.25 mm thickness), toluene:ethyl acetate=1:1, developedtwice) to give the titled compound (2.759 mg, 5.02%) as a colorless oil.IR(neat): 3390, 2964, 2927, 2879, 2852, 1728, 1462, 1377, 1360 cm⁻¹. ¹HNMR δ: 0.81-0.92 (m, 9H), 1.36 (s, 3H), 1.37 (s, 3H), 2.56-2.66 (m, 1H),2.76-2.86 (m, 1H), 3.39-3.57 (m, 2H), 4.19-4.30 (m, 1H), 4.39-4.50 (m,1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.63 (brs, 1H), 6.11 (d, J=11.2 Hz,1H), 6.38 (d, J=11.2 Hz, 1H). MS m/z: 343 (M⁺—(CH₂)₂CEt₂OH), 57 (100%).UV λ_(max) nm: 265.

Example 27

[0316] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(tert-butoxycarbonylmethoxymethyl)androsta-5,7,16-triene

[0317] A solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene(1.0 g, 1.84 mmol), sodium hydride (60% in oil, 220 mg, 5.50 mmol),15-crown-5 (400 mg, 1.82 mmol) and t-butyl bromoacetate (0.55 ml, 3.69mmol) in tetrahydrofuran (20 ml) was refluxed under heating for 1 hourand 15 min. The reaction solution was diluted with ethyl acetate andfiltered with CELITE. Under cooling with ice, water was added dropwiseto the filtrate which was then washed with saturated brine. The organiclayer was dried over anhydrous magnesium sulfate, evaporated underreduced pressure to remove the solvent and the thus obtained residue waspurified by column chromatography (hexane:ethyl acetate=20:1) to givethe titled compound (946.6 mg, 78%) as a colorless oil. IR(neat): 2952,2928, 2892, 2856, 1748, 1460, 1370, 1252, 1098, 968, 8 34, 774 cm⁻¹. ¹HNMR δ: 0.05 (s, 3H), 0.06 (s, 6H), 0.11 (s, 3H), 0.84 (s, 3H), 0.88 (s,18H), 0.94 (s, 3H), 1.48 (s, 9H), 2.79-2.92 (m, 1H), 3.70 (brs, 1H),3.95 (s, 2H), 4.13 (s, 2H), 3.97-4.20 (m, 1H), 5.35-5.43 (m, 1H), 5.60(d, J=5.4 Hz, 1H), 5.69 (s, 1H). MS m/z: 526 (M⁺—HOCH₂CO₂C(CH₃)₃), 57(100%). UV λ_(max) nm: 271, 281, 294.

[0318] (2) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(2-hydroxy-2-methylpropoxymethyl)androsta-5,7,16-triene

[0319] To a solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(tert-butoxycarbonylmethoxymethyl)androsta-5,7,16-triene(175 mg, 0.266 mmol) in tetrahydrofuran (4 ml), was added dropwise a0.93M methylmagnesium bromide/tetrahydrofuran solution (3 ml, 2.79 mmol)at external temperature of −30° C., followed by stirring at the sametemperature for 1 hour and 30 min. At the same temperature, a saturatedaqueous ammonium chloride solution was added to the reaction solution,which was then warmed to room temperature and stirred for 10 min. Waterwas added to the reaction solution, which was then extracted with ethylacetate. The organic layer was washed with a saturated aqueous sodiumbicarbonate solution and saturated brine, dried over anhydrous magnesiumsulfate and evaporated to remove the solvent under reduced pressure; thethus obtained residue was purified by preparative thin layerchromatography (3 sheets (each 0.5 mm thickness), hexane:ethylacetate=20:1, developed twice, hexane:ethyl acetate=15:1, developedtwice, and hexane:ethyl acetate 10:1, developed once) to give the titledcompound (115.3 mg, 70%) as a colorless oil. IR(neat): 3400, 2952, 2928,2892, 2856, 1462, 1372, 1254, 1096, 912, 834, 774 cm⁻¹. ¹H NMR δ: 0.05(s, 3H), 0.06 (s, 6H), 0.11 (s, 3H), 0.84 (s, 3H), 0.88 (s, 18H), 0.95(s, 3H), 1,21 (s, 6H), 2.79-2.93 (m, 1H), 3.26 (d, J=8.8 Hz, 1H), 3.29(d, J=8.8 Hz, 1H), 3.70 (brs, 1H), 3.96-4.17 (m, 3H), 5.36-5.44 (m, 1H),5.61 (d, J=5.4 Hz, 1H), 5.65 (brs, 1H). MS m/z: 616 (M⁺), 73 (100%). UVλ_(max) nm: 271, 281, 294.

[0320] (3) Synthesis of1α,3β-dihydroxy-17-(2-hydroxy-2-methylpropoxymethyl)androsta-5,7,16-triene

[0321]1α,30β-Bis(tert-butyldimethylsilyloxy)-17-(2-hydroxy-2-methylpropoxymethyl)androsta-5,7,16-triene(115 mg, 0.186 mmol), a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (1.2 ml, 1.2 mmol) and tetrahydrofuran (2.5 ml)were subjected to reaction using a procedure similar to that of Example5(2) (14 hours), worked up and the thus obtained residue was purified bypreparative thin layer chromatography (1 sheet (0.5 mm thickness),dichloromethane:ethanol=15:1, developed three times) to give the titledcompound (52.7 mg, 73%) as a colorless oil. IR(neat): 3416, 2932, 1452,1372, 1240, 1084, 912, 734 cm⁻¹. ¹H NMR δ: 0.84 (s, 3H), 0.98 (s, 3H),1.21 (s, 6H), 2.46-2.61 (m, 1H), 2.71-2.86 (m, 1H), 3.23 (d, J=8.7 Hz,1H), 3.28 (d, J=8.7 Hz, 1H), 3.77 (brs, 1H), 3.97-4.18 (m, 3H),5.40-5.55 (m, 1H), 5.65 (s, 1H), 5.69-5.78 (m, 1H). MS m/z: 389 (M⁺+1),59 (100%). UV λ_(max) nm: 271, 281, 293.

[0322] (4) Synthesis of1α,3β-dihydroxy-17-(2-hydroxy-2-methylpropoxymethyl)-9,10-secoandrosta-5,7,10(19),16-tetraene

[0323]1α,3β-Dihydroxy-17-(2-hydroxy-2-methylpropoxymethyl)androsta-5,7,16-triene(63.0 mg, 0.162 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 6min. 30 sec., reflux under heating for 1.5 hours) and purified bypreparative thin layer chromatography (1 sheet (0.5 mm thickness),dichloromethane:ethanol=15:1, developed three times; 1 sheet (0.25 mmthickness), toluene:ethyl acetate=5:6, developed twice, andtoluene:ethyl acetate=2:3, developed once; and 1 sheet (0.25 mmthickness), hexane:ethyl acetate:ethanol=10:5:1, developed three times)to give the titled compound (3.761 mg, 6%) as a colorless foam.IR(neat): 3368, 2928, 1444, 1368, 1106, 1060, 912, 732 cm⁻¹. ¹H NMR δ:0.74 (s, 3H), 1.21 (s, 3H), 2.54-2.67 (m, 1H), 2.75-2.89 (m, 1H), 3.23(d, J=8.8 Hz, 1H), 3.28 (d, J=8.8 Hz, 1H), 3.96-4.17 (m, 2H), 4.17-4.30(m, 2H), 4.37-4.51 (m, 1H), 5.01 (s, 1H), 5.34 (s, 1H), 5.61 (s, 1H),6.10 (d, J=11.2 Hz, 1H), 6.37 (d, J=11.2 Hz, 1H). MS m/z: 298(M⁺—HOCH₂C(CH₃)₂OH), 59 (100%). UV λ_(max) nm: 263.

Example 28

[0324] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(2-ethyl-2-hydroxybutoxymethyl)androsta-5,7,16-triene

[0325] A solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(tert-butoxycarbonylmethoxymethyl)androsta-5,7,16-triene(175 mg, 0.266 mmol) in tetrahydrofuran (4 ml) was subjected to reactionwith a 0.96M ethylmagnesium bromide/tetrahydrofuran solution (3 ml, 2.88mmol) using a procedure similar to that of Example 27(2) (externaltemperature of −30° C. for 1.5 hours), worked up and purified bypreparative thin layer chromatography (3 sheets (each 0.5 mm thickness),hexane:ethyl acetate=20:1, developed twice, hexane:ethyl acetate=15:1,developed twice, and hexane:ethyl acetate=10:1, developed once) to givethe titled compound (139.5 mg, 81%) as a colorless oil. IR(neat): 3480,2952, 2856, 1462, 1372, 1252, 1072, 968, 836, 774 cm⁻¹. ¹H NMR δ: 0.05(s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.84 (s, 3H), 0.88 (s, 18H), 0.95(s, 3H), 1.52 (q, J=7.3 Hz, 4H), 2.77-2.92 (m, 1H), 3.26 (d, J=9.1 Hz,1H), 3.32 (d, J=9.1 Hz, 1H), 3.71 (brs, 1H), 3.94-4.17 (m, 3H),5.35-5.44 (m, 1H), 5.61 (d, J=5.6 Hz, 1H), 5.64 (brs, 1H). MS m/z: 644(M⁺), 455 (100%). UV λ_(max) nm: 271, 281, 294.

[0326] (2) Synthesis of17-(2-ethyl-2-hydroxybutoxymethyl)-1α,3β-dihydroxyandrosta-5,7,16-triene

[0327]1α,3β-Bis(tert-butyldimethylsilyloxy)-17-{2-ethyl-2-hydroxybutoxymethyl}androsta-5,7,16-triene(139 mg, 0.216 mmol), a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (1.3 ml, 1.3 mmol) and tetrahydrofuran (3 ml)were subjected to reaction using a procedure similar to that of Example5(2) (4 hours), worked up and the thus obtained residue was purified bypreparative thin layer chromatography (1 sheet (0.5 mm thickness),dichloromethane:ethanol=10:1, developed three times) to give the titledcompound (64.4 mg, 72%) as a colorless oil. IR(neat): 3388, 2968, 2932,1462, 1370, 1058, 946, 736 cm⁻¹. ¹H NMR δ: 0.83 (s, 3H), 0.87 (t, J=7.4Hz, 6H), 0.98 (s, 3H), 1.52 (q, J=7.4 Hz, 4H), 2.48-2.62 (m, 1H),2.76-2.87 (m, 1H), 3.26 (d, J=9.1 Hz, 1H), 3.32 (d, J=9.1 Hz, 1H), 3.78(brs, 1H), 4.00-4.23 (m, 3H), 5.40 -5.52 (m, 1H), 5.64 (s, 1H),5.70-5.77 (m, 1H). MS m/z: 416 (M⁺), 87 (100%). UV λ_(max) nm: 271, 281,293.

[0328] (3) Synthesis of17-(2-ethyl-2-hydroxybutoxymethyl)-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene

[0329]17-(2-Ethyl-2-hydroxybutoxymethyl)-1α,3β-dihydroxyandrosta-5,7,16-triene(89 mg, 0.214 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 9min., reflux under heating for 1.5 hours) and purified by preparativethin layer chromatography (1 sheet (0.5 mm thickness),dichloromethane:ethanol=15:1, developed three times; 1 sheet (0.25 mmthickness), toluene:ethyl acetate=5:6, developed twice, andtoluene:ethyl acetate=2:3, developed once; and 1 sheet (0.25 mmthickness), hexane:ethyl acetate:ethanol=10:5:1, developed three times)to give the titled compound (4.941 mg, 6%) as a colorless foam.IR(neat): 3375, 2928, 1454, 1342, 1056, 912, 730 cm⁻¹. ¹H NMR δ: 0.73(s, 3H), 0.87 (s, 3H), 0.87 (t, J=7.5 Hz, 6H), 1.52 (q, J=7.5 Hz, 4H),2.53-2.68 (m, 1H), 2.75-2.90 (m, 1H), 3.26 (d, J=9.0 Hz, 1H), 3.31 (d,J=9.0 Hz, 1H), 3.92-4.15 (m, 2H), 4.17-4.32 (m, 1H), 4.37-4.52 (m, 1H),5.01 (s, 1H), 5.34 (s, 1H), 5.60 (s, 1H), 6.10 (d, J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). MS m/z: 298 (M⁺—HOCH₂C(CH₂CH₃)₂OH), 87 (100%). UVλ_(max) nm: 262.

Example 29

[0330] (1) Synthesis of1α,3β-dihydroxy-17-{4-hydroxy-4-methyl-(2Z)-pentenyloxymethyl}androsta-5,7,16-triene

[0331]1α,3β-Dihydroxy-17-(4-hydroxy-4-methyl-2-pentynyloxymethyl)androsta-5,7,16-triene(78 mg, 0.189 mmol), quinoline (12.3 mg, 0.0952 mmol), 5%palladium/barium sulfate (16 mg) and methanol (5 ml) were stirred atroom temperature for 2 hours under a hydrogen atmosphere. The reactionmixture was filtered, evaporated for remove the solvent and purified bycolumn chromatography (dichloromethane: methanol=20:1) to give thetitled compound (61 mg, 78%) as a colorless glassy substance. IR(neat):3369, 2970, 2929, 2852, 1458, 1369, 1173, 1151, 1080, 1055 cm⁻¹. ¹H NMRδ: 0.84 (s, 3H), 0.98 (s, 3H), 1.34 (s, 6H), 2.73-2.85 (m, 1H),3.50-3.58 (br, 1H), 3.75-3.81 (br, 1H), 3.99-4.26 (m, 5H), 5.42-5.52 (m,2H), 5.63 (brs, 1H), 5.68 (brs, 1H), 5.74 (brd, J=5.9 Hz, 1H). MS m/z:396 (M⁺—H₂O), 55 (100%). UV λ_(max) nm: 271, 281, 293.

[0332] (2) Synthesis of1α,3β-dihydroxy-17-{4-hydroxy-4-methyl-(2Z)-pentenyloxymethyl}-9,10-secoandrosta-5,7,10(19),16-tetraene

[0333]1α,3β-Dihydroxy-17-{4-hydroxy-4-methyl-(2Z)-pentenyloxymethyl}androsta-5,7,16-triene(60 mg, 0.145 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 4min. 45 sec., reflux under heating for 2 hours) and purified bypreparative thin layer chromatography (2 sheets (each 0.5 mm thickness),dichloromethane:ethanol=10:1, developed twice; and 1 sheet (0.5 mmthickness), toluene:ethyl acetate 1:1, developed twice) to give thetitled compound (4.00 mg, 7%) as a colorless glassy substance. IR(neat):3363, 2968, 2929, 2850, 1435, 1369, 1173, 1057 cm⁻¹. ¹H NMR δ: 0.74 (s,3H), 1.34 (s, 6H), 2.75-2.87 (m, 1H), 3.99-4.28 (m, 5H), 4.39-4.49 (br,1H), 5.01 (brs, 1H), 5,34 (brs, 1H), 5.41-5.70 (m, 3H), 6.10 (d, J=11.2Hz, 1H), 6.36 (d, J=11.2 Hz, 1H). MS m/z: 396 (M⁺—H₂O), 55 (100%). UVλ_(max) nm: 263.

Example 30

[0334] (1) Synthesis of17-{4-ethyl-4-hydroxy-(2Z)-hexenyloxymethyl}-1α,3β-dihydroxyandrosta-5,7,16-triene

[0335] The fraction (0.3 g) containing17-(4-ethyl-4-hydroxy-2-hexynyloxymethyl)-1α,3β-dihydroxyandrosta-5,7,16-trieneobtained in Example 11 (2), 5% palladium/barium sulfate (0.3 g),quinoline (0.03 ml, 0.2538 mmol) and methanol (6.8 ml) were subjected toreaction using a procedure similar to that of Example 29(1) (4 hours)and worked up to give a mixture (0.80 mg) containing the targetedcompound.

[0336] (2) Synthesis of17-{4-ethyl-4-hydroxy-(2Z)-hexenyloxymethyl}-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene

[0337] Ethanol (200 ml) and the mixture (0.80 mg) containing17-{4-ethyl-4-hydroxy-(2Z)-hexenyloxymethyl}-1α,3β-dihydroxyandrosta-5,7,16-trieneobtained in the above (1) were subjected to reaction using a proceduresimilar to that of Example 5(3) (irradiation for 4 min. 45 sec., refluxunder heating for 2 hours) and purified by preparative thin layerchromatography (4 sheets (each 0.5 mm thickness),dichloromethane:ethanol=9:1, developed once; and 4 sheets (each 0.5 mmthickness), ethyl acetate:toluene=1:1, developed once) to give thetitled compound (3.41 mg, 4%) as a colorless oil. IR(neat): 3566, 2854,1458, 1257 cm⁻¹. ¹H NMR δ: 0.73 (s, 3H), 0.90 (t, J=7.3 Hz, 6H), 4.04(brs, 2H), 4.18-4.28 (m, 3H), 4.44 (brs, 1H), 5.01 (s, 1H), 5.33 (s,1H), 5.41-5.67 (m, 3H), 6.09 (d, J=11.6 Hz, 1H), 6.37 (d, J=11.6 Hz,1H). MS m/z: 424 (M⁺—H₂O), 57 (100%). UV λ_(max) nm: 264.

Example 31

[0338] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-{4-ethyl-4-(triethylsilyloxy)hexylthiomethyl}androsta-5,7,16-triene

[0339] To a solution of17-acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triene(274 mg, 0.454 mmol) and 1-bromo-4-ethyl-4-(triethylsilyloxy)hexane (294mg, 0.909 mmol) in tetrahydrofuran (2 ml), was added a 1M potassiumhydroxide methanol solution (3 ml) under a nitrogen atmosphere, followedby stirring at room temperature for 5 min. The thus obtained reactionmixture was partitioned by adding ethyl acetate and water. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate and evaporated to remove the solvent under reduced pressure. Thethus obtained residue was purified by column chromatography(hexane:toluene=6:1) to give the titled compound (333 mg, 91%) as acolorless oil. IR(neat): 2954, 2929, 2879, 2856, 1462, 1371, 1254, 1099,1072 cm⁻¹. ¹H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.57 (q,J=7.9 Hz, 6H), 0.88 (s, 18H), 0.95 (t, J=7.9 Hz, 9H), 1.45 (q, J=7.6 Hz,4H), 2.78-2.91 (m, 1H), 3.19 (s, 2H), 3.71 (brs, 1H), 3.97-4.13 (m, 1H),5.35-5.43 (m, 1H), 5.54-5.56 (m, 2H). MS m/z: 803 (M⁺+1), 73 (100%). UVλ_(max) nm: 271, 281, 294.

[0340] (2) Synthesis of17-(4-ethyl-4-hydroxyhexylthiomethyl)-1α,3β-dihydroxyandrosta-5,7,16-triene

[0341]1α,3β-Bis(tert-butyldimethylsilyloxy)-17-{4-ethyl-4-(triethylsilyloxy)hexylthiomethyl}androsta-5,7,16-triene(310 mg, 0.386 mmol) and a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (5 ml) were subjected to reaction using aprocedure similar to that of Example 5(2) (3 hours), worked up andpurified by column chromatography (ethyl acetate) to give the titledcompound (136 mg, 77%) as a colorless foam. IR(neat): 3370, 2964, 2935,2879, 2850, 1458, 1369, 1196, 1109, 1053, 1032 cm⁻¹. ¹H NMR δ: 0.86 (t,J=7.3 Hz, 6H), 0.99 (s, 3H), 1.47 (q, J=7.3 Hz, 4H), 2.73-2.86 (m, 1H),3.12-3.27 (m, 2H), 3.79 (brs, 1H), 4.01-4.16 (m, 1H), 5.43-5.49 (m, 1H),5.58 (s, 1H), 5.75 (dd, J=5.6, 1.7 Hz, 1H). MS m/z: 460 (M⁺),143 (100%).UV λ_(max) nm: 271, 281, 293.

[0342] (3) Synthesis of17-(4-ethyl-4-hydroxyhexylthiomethyl)-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene

[0343]17-(4-Ethyl-4-hydroxyhexylthiomethyl)-1α,3β-dihydroxyandrosta-5,7,16-triene(130 mg, 0.282 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 7min., reflux under heating for 2 hours) and purified by preparative thinlayer chromatography (3 sheets (each 0.5 mm thickness),dichloromethane:ethanol=10:1, developed twice; and 2 sheets (each 0.5 mmthickness), toluene:ethyl acetate=5:6, developed twice) to give thetitled compound (6.52 mg, 5%) as a colorless foam. IR(neat): 3350, 2962,2929, 2879, 2846, 1456, 1367, 1338, 1055 cm⁻¹. ¹H NMR δ: 0.75 (s, 3H),0.86 (t, J=7.6 Hz, 6H), 1.47 (q, J=7.6 Hz, 4H), 2.74-2.89 (m, 1H),3.10-3.25 (m, 2H), 4.19-4.29 (m, 1H), 4.40-4.50 (m, 1H), 5.01 (brs, 1H),5.34 (brs, 1H), 5.54 (brs, 1H), 6.10 (d, J=11.2 Hz, 1H), 6.37 (d, J=11.2Hz, 1H). MS m/z: 442 (M⁺—H₂O), 57 (100%). UV λ_(max) nm: 263.

Example 32

[0344] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-{5-(triethylsilyloxy)-5-methylhexylthiomethyl}androsta-5,7,16-triene

[0345]17-Acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triene(262 mg, 0.434 mmol), 1-bromo-5-triethylsilyloxy-5-methylhexane (266 mg,0.860 mmol), a 1M potassium hydroxide methanol solution (3 ml) andtetrahydrofuran (2 ml) were subjected to reaction using a proceduresimilar to that of Example 31(1) (3 hours at room temperature), workedup and purified by column chromatography (hexane:toluene=4:1) to givethe titled compound (320 mg, 93%) as a colorless oil. IR(neat): 2954,2931, 2856, 1458, 1363, 1254, 1099, 1072, 1053 cm⁻¹. ¹H NMR δ: 0.05 (s,6H), 0.07 (s, 6H), 0.11 (s, 3H), 0.56 (q, J=7.9 Hz, 6H), 0.88 (s, 18H),1.19 (s, 6H), 2.80-2.91 (m, 1H), 3.19 (s, 2H), 3.71 (brs, 1H), 3.97-4.11(m, 1H), 5.36-5.42 (m, 1H), 5.56-5.63 (m, 2H). MS m/z: 788 (M⁺+1), 73(100%). UV λ_(max) nm: 271, 282, 294.

[0346] (2) Synthesis of1α,3β-dihydroxy-17-(5-hydroxy-5-methylhexylthiomethyl)androsta-5,7,16-triene

[0347]1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(5-triethylsilyloxy-5-methylhexylthiomethyl)androsta-5,7,16-triene(313 mg, 0.396 mmol) and a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (5 ml) were subjected to reaction using aprocedure similar to that of Example 5(2) (3 hours), worked up andpurified by column chromatography (ethyl acetate) to give the titledcompound (152 mg, 86%) as a colorless solid. IR(neat): 3370, 2968, 2935,2846, 1462, 1367, 1228, 1194, 1149, 1055 cm⁻¹. ¹H NMR δ: 0.86 (s, 3H),0.99 (s, 3H), 1.22 (s, 6H), 2.73-2.85 (m, 1H), 3.11-3.26 (m, 2H), 3.79(brs, 1H), 3.99-4.15 (m, 1H), 5.42-5.49 (m, 1H), 5.58 (brs, 1H), 5.75(brd, J=5.6 Hz, 1H). MS m/z: 446 (M⁺), 280 (100%). UV λ_(max) nm: 271,282, 294.

[0348] (3) Synthesis of1α,3β-dihydroxy-17-(5-hydroxy-5-methylhexylthiomethyl)-9,10-secoandrosta-5,7,10(19),16-tetraene

[0349]1α,3β-Dihydroxy-17-(5-hydroxy-5-methylhexylthiomethyl)androsta-5,7,16-triene(140 mg, 0.282 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 7min. 30 sec., reflux under heating for 2 hours) and purified bypreparative thin layer chromatography (3 sheets (each 0.5 mm thickness),dichloromethane:ethanol=10:1, developed twice; and 2 sheets (each 0.5 mmthickness), toluene:ethyl acetate=5:6, developed three times) to givethe titled compound (7.24 mg, 5%) as a colorless foam. IR(neat): 3340,2962, 2931, 2846, 1441, 1367, 1144, 1055 cm⁻¹. ¹H NMR δ: 0.75 (s, 3H),1.22 (s, 6H), 2.75-2.89 (m, 1H), 3.09-3.24 (m, 2H), 4.19-4.29 (br, 1H),4.40-4.49 (br, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.54 (brs, 1H), 6.10(d, J=11.2 Hz, 1H), 6.37 (d, J=11.2 Hz, 1H). MS m/z: 298(M⁺—HS(CH₂)₄C(CH₃)₂OH), 59 (100%). UV λ_(max) nm: 263.

Example 33

[0350] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-{4-triethylsilyloxy-4-methyl-(2E-pentenylthiomethyl}androsta-5,7,16-triene

[0351]17-Acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triene(304 mg, 0.504 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-(2E)-pentene(296 mg, 1.01 mmol), a 1M potassium hydroxide methanol solution (3 ml)and tetrahydrofuran (2 ml) were subjected to reaction using a proceduresimilar to that of Example 31(1) (at room temperature for 10 min.),worked up and purified by column chromatography (hexane:toluene=6:1) togive the titled compound (351 mg, 90%) as a pale yellow solid. IR(neat):2954, 2929, 2856, 1462, 1373, 1254, 1099, 1072, 1051, 1007 cm⁻¹. ¹H NMRδ: 0.05 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.57 (q, J=7.9 Hz, 6H),0.85 (s, 3H), 0.88 (s, 18H), 0.94 (t, J=7.9 Hz, 9H), 1.31 (s, 6H),2.80-2.90 (m, 1H), 3.09 (d, J=6.3 Hz, 2H), 3.13 (brs, 2H), 3.71 (brs,1H), 3.98-4.11 (m, 1H), 5.35-5.42 (m, 1H), 5.48-5.70 (m, 4H). MS m/z:772 (M⁺), 73 (100%). UV λ_(max) nm: 271, 282, 294.

[0352] (2) Synthesis of1α,3β-dihydroxy-17-{4-hydroxy-4-methyl-(2E)-pentenylthiomethyl}androsta-5,7,16-triene

[0353]1α,3β-Bis(tert-butyldimethylsilyloxy)-17-{4-triethylsilyloxy-4-methyl-(2E)-pentenylthiomethyl}androsta-5,7,16-triene(115 mg, 0.149 mmol) and a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (4 ml) were subjected to reaction using aprocedure similar to that of Example 5(2) (3 hours), worked up andpurified by column chromatography (ethyl acetate) to give the titledcompound (64 mg, 100%) as a pale yellow foam. IR(neat): 3372, 3035,2968, 2925, 2850, 1458, 1369, 1230, 1151, 105 3, 1034 cm⁻¹. ¹H NMRδ:0.86 (s, 3H), 0.98 (s, 3H), 1.34 (s, 6H), 2.74-2.85 (m ,1H), 3.10 (d,J=6.3 Hz, 2H), 3.14 (brs, 2H), 3.79 (brs, 1H), 3.99-4.15 (m, 1H),5.43-5.49 (m, 1H), 5.56-5.78 (m, 4H). MS m/z: 412 (M⁺—H₂O), 279 (100%).UV λ_(max) nm: 271, 282, 293.

[0354] (3) Synthesis of1α,3β-dihydroxy-17-{4-hydroxy-4-methyl-(2E)-pentenylthiomethyl}-9,10-secoandrosta-5,7,10(19),16-tetraene

[0355]1α,3β-Dihydroxy-17-{4-hydroxy-4-methyl-(2E)-pentenylthiomethyl}androsta-5,7,16-triene(61 mg, 0.142 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 4min. 45 sec., reflux under heating for 2 hours) and purified bypreparative thin layer chromatography (2 sheets (each 0.5 mm thickness),dichloromethane:ethanol=10:1, developed twice; 1 sheet (0.5 mmthickness), toluene:ethyl acetate=5:6, developed twice; and 1 sheet (0.5mm thickness), hexane:ethyl acetate:ethanol=10:10:1, developed twice) togive the titled compound (7.24 mg, 5%) as a colorless foam. IR(neat):3380, 2924, 2850, 1590, 1363, 1120 cm⁻¹. ¹H NMR δ: 0.75 (s, 3H), 1.34(s, 6H), 2.77-2.87 (m, 1H), 3.07-3.13 (m, 4H), 4.18-4.29 (m, 1H),4.40-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.52-5.74 (m, 3H),6.10 (d, J=11.2 Hz, 1H), 6.37 (d, J=11.2 Hz, 1H). MS m/z: 430 (M⁺), 91(100%). UV λ_(max) nm: 264.

Example 34

[0356] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-(3-hydroxy-3-methylbutylthiomethyl)androsta-5,7,16-triene

[0357]17-Acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triene(67.7 mg, 0.112 mmol), 1-bromo-3-hydroxy-3-methylbutane (93.5 mg, 0.560mmol), 1M potassium hydroxide methanol solution (1 ml) andtetrahydrofuran (1 ml) were subjected to reaction using a proceduresimilar to that of Example 31(1) (at room temperature for 30 min.),worked up and purified by preparative thin layer chromatography (2sheets (each 0.5 mm thickness), hexane:ethyl acetate=3:1, developedonce) to give the titled compound (67.4 mg, 93%) as a colorless oil.IR(neat): 3417, 2956, 2929, 2856, 1471, 1462, 1371, 1254, 1099, 1074cm⁻¹. ¹H NMR δ: 0.05 (s, 3H), 0.07 (s, 3H), 0.07 (s, 3H), 0.11 (s, 3H),0.85 (s, 3H), 0.88 (s, 9H), 0.89 (s, 9H), 0.95 (s, 3H), 1.24 (s, 6H),2.59 (m, 2H), 2.85 (m, 1H), 3.23 (m, 2H), 3.71 (brs, 1H), 3.98-4.12 (m,1H), 5.36-5.42 (m, 1H), 5.56-5.64 (m, 2H). MS m/z: 646 (M⁺), 457 (100%).UV λ_(max) nm: 271, 281, 294.

[0358] (2) Synthesis of1α,3β-dihydroxy-17-(3-hydroxy-3-methylbutylthiomethyl)androsta-5,7,16-triene

[0359]1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(3-hydroxy-3-methylbutylthiomethyl)androsta-5,7,16-triene(63.5 mg, 0.0981 mmol), a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (1 ml) and tetrahydrofuran (1 ml) weresubjected to reaction using a procedure similar to that of Example 5(2)(reflux under heating for 5.5 hours), worked up and purified bypreparative thin layer chromatography (2 sheets (each 0.5 mm thickness),dichloromethane:ethanol=9:1, developed once) to give the titled compound(39.2 mg, 95%) as a colorless oil. IR(neat): 3396, 2968, 2629, 2850,1462, 1369, 1207, 1151, 1055 cm⁻¹. ¹H NMR δ: 0.86 (s, 3H), 0.98 (s, 3H),1.24 (s, 6H), 2.58 (m, 2H), 2.79 (m, 1H), 3.23 (m, 2H), 3.78 (brs, 1H),3.99-4.11 (m, 1H), 5.42-5.48 (m, 1H), 5.59 (brs, 1H), 5.73 (brd, J=5.9Hz, 1H). MS m/z: 418 (M⁺), 298 (100%). UV λ_(max) nm: 271, 281, 293.

[0360] (3) Synthesis of1α,3β-dihydroxy-17-(3-hydroxy-3-methylbutylthiomethyl)-9,10-secoandrosta-5,7,10(19),16-tetraene

[0361]1α,3β-Dihydroxy-17-(3-hydroxy-3-methylbutylthiomethyl)androsta-5,7,16-triene(37.0 mg, 0.0884 mmol) and ethanol (200 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 4min. 15 sec., reflux under heating for 2 hours) and purified bypreparative thin layer chromatography (1 sheet (0.5 mm thickness),dichloromethane:ethanol=9:1, developed twice; 1 sheet (0.25 mmthickness), hexane:ethyl acetate:ethanol=5:5:1, developed twice; and 1sheet (0.25 mm thickness), dichloromethane:ethyl acetate:ethanol=14:6:1,developed twice) to give the titled compound (0.764 mg, 2.1%) as acolorless oil. IR(neat): 3367, 2925, 2850, 1437, 1367, 1288, 1209, 1146,1055 cm⁻¹. ¹H NMR δ: 0.76 (s, 3H), 1.24 (s, 6H), 2.58 (m, 2H), 2.82 (m,1H), 3.21 (m, 2H), 4.18-4.30 (br, 1H), 4.38-4.49 (br, 1H), 5.01 (brs,1H), 5.34 (brs, 1H), 5.56 (brs, 1H), 6.10 (d, J=11.2 Hz, 1H), 6.37 (d,J=11.2 Hz, 1H). MS m/z: 418 (M⁺), 133 (100%). UV λ_(max) nm: 263.

Example 35

[0362] (1) Synthesis of1α,3β-bis(tert-butyldimethylsilyloxy)-17-hydroxymethyl-9,10-secoandrosta-5,7,10(19),16-tetraene

[0363]1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene(750 mg, 1.38 mmol) and ethanol (600 ml) were subjected to reactionusing a procedure similar to that of Example 5(3) (irradiation for 30min., reflux under heating for 2 hours) and purified by columnchromatography (hexane:ethyl acetate=10:1) to give a fraction (550 mg)containing the titled compound.

[0364] (2) Synthesis of17-acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)-9,10-secoandrosta-5,7,10(19),16-tetraene

[0365] The1α,3β-bis(tert-butyldimethylsilyloxy)-17-hydroxymethyl-9,10-secoandrosta-5,7,10(19),16-tetraene-containingfraction (550 mg), methanesulfonyl chloride (0.23 ml, 2.97 mmol),triethylamine (0.56 ml, 4.02 mmol), tetrahydrofuran (5 ml), potassiumthioacetate (0.457 g, 4.00 mmol) and dimethylsulfoxide (5 ml) weresubjected to reaction using a procedure similar to that of Example 1(3)(mesylation for 15 min. and thioacetylation for 30 min.), worked up andpurified by preparative thin layer chromatography (7 sheets (each 1.0 mmthickness), hexane:ethyl acetate=10:1, developed once) to give afraction (430 mg) containing the titled compound.

[0366] (3)17-acetylthiomethyl-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene

[0367] The fraction (430 mg) containing17-acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)-9,10-secoandrosta-5,7,10(19),16-tetraeneobtained in the above (2) was dissolved in tetrahydrofuran (40 ml). Theresulting solution was mixed with methanol (40 ml) and AMBERLYST 15 (18g) under a nitrogen atmosphere, stirred at room temperature for 4 hoursand filtered with CELITE. The thus obtained filtrate was mixed withsodium bicarbonate (100 mg) and stirred at room temperature for 5 min.After filtering off the sodium bicarbonate, the resulting filtrate wasevaporated under reduced pressure to remove the solvent and purified bypreparative thin layer chromatography (7 sheets (each 1.0 mm thickness),hexane:ethyl acetate:ethanol=5:5:1, developed once) to give the titledcompound (30 mg, 5.8%, in 3 steps) as a colorless oil. ¹H NMR δ: 0.72(s, 3H), 2.33 (s, 3H), 3.50-3.68 (m, 2H), 4.10 (brs, 1H), 4.43 (brs,1H), 5.00 (s, 1H), 5.33 (s, 1H), 5.57 (s, 1H), 6.10 (d, J=11.2 Hz, 1H),6.34 (d, J=11.2 Hz, 1H).

[0368] (4)17-(3-ethyl-3-hydroxypentylthiomethyl)-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene

[0369]17-Acetylthiomethyl-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene(10 mg, 0.0267 mmol), 1-bromo-3-ethyl-3-hydroxypentane (10 mg, 0.0513mmol), a 1M potassium hydroxide methanol solution (0.5 ml) andtetrahydrofuran (0.5 ml) were subjected to reaction using a proceduresimilar to that of Example 31(1) (15 min.), worked up and purified bypreparative thin layer chromatography (1 sheet (0.5 mm thickness),hexane:ethyl acetate=1:1, developed once; and 1 sheet (0.5 mmthickness), ethyl acetate:toluene=1:1, developed once) to give thetitled compound (3.60 mg, 30%) as a colorless oil. IR(neat): 3446, 2962,2362, 1055 cm⁻¹. ¹H NMR δ: 0.76 (s, 1H), 0.87 (t, J=7.6 Hz, 6H), 3.20(brs, 2H), 4.25 (brs, 1H), 4.44 (brs, 1H), 5.01 (s, 1H), 5.34 (s, 1H),5.56 (brs, 1H), 6.10 (d, J=11.2 Hz, 1H), 6.37 (d, J=11.2 Hz, 1H). MSm/z: 428 (M⁺—H₂O), 57 (100%). UV λ_(max) nm: 264.

Example 36

[0370]1α,3β-dihydroxy-17-(2-hydroxy-2-methylpropylthiomethyl)-9,10-secoandrosta-5,7,10(19),16-tetraene

[0371]17-Acetylthiomethyl-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene(5 mg, 0.0133 mmol), 1,2-epoxy-2-methylpropane (20 mg, 0.277 mmol), a 1Mpotassium hydroxide methanol solution (0.5 ml) and tetrahydrofuran (0.1ml) were subjected to reaction using a procedure similar to that ofExample 31(1) (at room temperature for 30 min.), worked up and purifiedby preparative thin layer chromatography (1 sheet (0.5 mm thickness),toluene:ethyl acetate=5:6, developed once) to give the titled compound(2.40 mg, 45%) as a colorless foam. IR(neat): 3360, 2966, 2927, 2848,1437, 1367, 1144, 1055 cm⁻¹. ¹H NMR δ: 0.75 (s, 3H), 1.28 (s, 6H), 2.62(s, 2H), 2.75-2.89 (m, 1H), 3.16-3.33 (m, 2H), 4.17-4.30 (m, 1H),4.40-4.51 (br, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.58 (brs, 1H), 6.11(d, J=11.2 Hz, 1H), 6.37 (d, J=11.2 Hz, 1H). MS m/z: 404 (M⁺), 59(100%). UV λ_(max) nm: 264.

Example 37

[0372]17-(2-ethyl-2-hydroxybutylthiomethyl)-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene

[0373]17-Acetylthiomethyl-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene(5 mg, 0.0133 mmol), 1,2-epoxy-2-ethylbutane (33 mg, 0.329 mmol), a 1Mpotassium hydroxide methanol solution (0.5 ml) and tetrahydrofuran (0.1ml) were subjected to reaction using a procedure similar to that ofExample 31(1) (at room temperature for 10 min.), worked up and purifiedby preparative thin layer chromatography (1 sheet (0.5 mm thickness),toluene:ethyl acetate 32 1:1, developed once) to give the titledcompound (3.27 mg, 57%) as a colorless glassy substance. IR(neat): 3370,2962, 2927, 2879, 2848, 1456, 1417, 1367, 1140, 1055 cm⁻¹. ¹H NMR δ:0.75 (s, 3H), 0.88 (t, J=7.6 Hz, 6H), 2.62 (s, 2H), 2.77-2.90 (m, 1H),3.15-3.29 (m, 2H), 4.18-4.30 (br, 1H), 4.40-4.50 (br, 1H), 5.01 (brs,1H), 5.34 (brs, 1H), 5.58 (brs, 1H), 6.10 (d, J=11.2 Hz, 1H), 6.37 (d,J=11.2 Hz, 1H). MS m/z: 432 (M⁺), 87 (100%). UV λ_(max) nm: 264.

Example 38

[0374]1α,3β-dihydroxy-17-{(2R)-hydroxy-3-methylbutylthiomethyl}-9,10-secoandrosta-5,7,10(19),16-tetraene

[0375]17-Acetylthiomethyl-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene(5 mg, 0.0133 mmol), (2R)-1,2-epoxy-3-methylbutane (29 mg, 0.337 mmol),a 1M potassium hydroxide methanol solution (0.5 ml) and tetrahydrofuran(0.1 ml) were subjected to reaction using a procedure similar to that ofExample 31(1) (at room temperature for 30 min.), worked up and purifiedby preparative thin layer chromatography (1 sheet (0.5 mm thickness),hexane:ethyl acetate=1:1, developed once) to give the titled compound(2.88 mg, 52%) as a colorless foam. IR(neat): 3370, 2956, 2923, 2848,1433, 1367, 1227, 1113, 1053, 1007 cm⁻¹. ¹H NMR δ: 0.73 (s, 3H), 0.93(d, J=6.9 Hz, 3H), 0.97 (d, J=6.9 Hz, 3H), 3.13 (d, J=14.9 Hz, 1H), 3.23(d, J=14.9 Hz, 1H), 3.35-3.44 (m, 1H), 4.18-4.29 (m, 1H), 4.40-4.49 (m,1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.55 (brs, 1H), 6.10 (d, J=11.2 Hz,1H), 6.37 (d, J=11.2 Hz, 1H). MS m/z: 298 (M⁺—HSCH₂CH(OH)CH(CH₃)₂), 55(100%). UV λ_(max) nm: 263.

Example 39

[0376]1α,3β-dihydroxy-17-(4-hydroxy-4-methyl-2-pentynylthiomethyl)-9,10-secoandrosta-5,7,10(19),16-tetraene

[0377]17-Acetylthiomethyl-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene(6 mg, 0.0160 mmol), 1-bromo-4-hydroxy-4-methyl-2-pentyne (10 mg, 0.0565mmol), a 1M potassium hydroxide methanol solution (0.5 ml) andtetrahydrofuran (0.5 ml) were subjected to reaction using a proceduresimilar to that of Example 31(1) (at room temperature for 10 min.,),worked up and purified by preparative thin layer chromatography (1 sheet(0.5 mm thickness), toluene:ethyl acetate=5:6, developed twice) to givethe titled compound (4.99 mg, 73%) as a colorless glassy substance.IR(neat): 3350, 2974, 2929, 2848, 1365, 1167, 1055 cm⁻¹. ¹H NMR δ: 0.76(s, 3H),1.52 (s, 6H),2.76-2.87 (m, 1H), 3.22 (s, 2H), 3.24-3.40 (m, 2H),4.18-4.31 (m, 1H), 4.40-4.49 (m, 1H),5.01 (brs, 1H), 5.34 (brs, 1H),5.59 (brs, 1H), 6.11 (d, J=11.2 Hz, 1H), 6.37 (d, J=11.2 Hz, 1H). MSm/z: 410 (M⁺—H₂O),91 (100%). UV λ_(max) nm: 264.

Example 40

[0378]17-(4-ethyl-4-hydroxy-2-hexynylthiomethyl)-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene

[0379] 17-Acetylthiomethyl-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19), 16-tetraene (5 mg, 0.0134 mmol),1-bromo-4-ethyl-4-hydroxy-2-hexyne (10 mg, 0.04876 mmol), a 1M potassiumhydroxide methanol solution (0.5 ml) and tetrahydrofuran (0.5 ml) weresubjected to reaction using a procedure similar to that of Example 31(1)(10 min.), worked up and purified by preparative thin layerchromatography (1 sheet (0.5 mm thickness), hexane:ethyl acetate=1:1,developed once; and 1 sheet (0.5 mm thickness),dichloromethane:ethanol=20:1, developed once) to give the titledcompound (3.30 mg, 54%) as a colorless oil. IR(neat): 3361, 2929, 1455,1052 cm⁻¹. ¹H NMR δ: 0.76 (s, 3H), 1.04 (t, J=7.3 Hz, 6H), 3.24 (s, 2H),3.32 (m, 2H), 4.22 (m, 1H), 4.43 (m, 1H), 5.01 (s, 1H), 5.34 (s, 1H),5.59 (brs, 1H), 6.11 (d, J=11.5 Hz, 1H), 6.37 (d, J=11.5 Hz, 1H). MSm/z: 438 (M⁺—H₂O), 57 (100%). UV λ_(max) nm: 263.

Example 41

[0380]17-{4-ethyl-4-hydroxy-(2E)-hexenylthiomethyl}-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene

[0381]17-Acetylthiomethyl-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene(10 mg, 0.0267 mmol), 1-bromo-4-ethyl-4-hydroxy-(2E)-hexene (10 mg,0.0483 mmol), a 1M potassium hydroxide methanol solution (0.5 ml) andtetrahydrofuran (0.5 ml) were subjected to reaction using a proceduresimilar to that of Example 31(1) (30 min.), worked up and purified bypreparative thin layer chromatography (1 sheet (0.5 mm thickness),hexane:ethyl acetate=1:1, developed once; and 1 sheet (0.5 mmthickness), ethyl acetate:toluene=1:1, developed once) to give thetitled compound (5.09 mg, 42%) as a colorless oil. IR(neat): 3465, 2925,2852 cm⁻¹. ¹H NMR δ: 0.75 (s, 3H), 0.88 (t, J=7.6 Hz, 6H), 3.01-3.16 (m,4H), 4.24 (m, 1H), 4.44 (brs, 1H), 5.01 (s, 1H), 5.34 (s, 1H), 5.45-5.69(m, 3H), 6.10 (d, J=11.2 Hz, 1H), 6.37 (d, J=11.2 Hz, 1H). MS m/z: 440(M⁺—H₂O), 57 (100%). UV λ_(max) nm: 263.

Example 42

[0382] (1) 17-(4-triethylsilyloxy-4-methylpentylthiomethyl)-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene

[0383]1α,3β-Dihydroxy-17-acetylthiomethyl-9,10-secoandrosta-5,7,10(19),16-tetraene(5 mg, 0.0133 mmol), 1-bromo-4-triethylsilyloxy-4-methylpentane (70 mg,0.226 mmol), a 1M potassium hydroxide methanol solution (1 ml) andtetrahydrofuran (0.1 ml) were subjected to reaction using a proceduresimilar to that of Example 31(1) (at room temperature for 30 min.) andworked up to give a mixture (5 mg) containing the titled compound.

[0384] (2)1α,3β-dihydroxy-17-(4-hydroxy-4-methylpentylthiomethyl)-9,10-secoandrosta-5,7,10(19),16-tetraene

[0385] The mixture (5 mg) obtained in the above (1), AMBERLYST 15 (1 g),methanol (5 ml) and tetrahydrofuran (5 ml) were subjected to reactionusing a procedure similar to that of Example 35(3) (at room temperaturefor 20 min.), worked up and purified by preparative thin layerchromatography (1 sheet (0.5 mm thickness),dichloromethane:ethanol=40:3, developed once) to give the titledcompound (2.85 mg, 49%) as a colorless glassy substance. IR(neat): 3380,2962, 2848, 1435, 1367, 1296, 1146, 1055 cm⁻¹. ¹H NMR δ: 0.75 (s, 3H),1.22 (s, 6H), 2.77-2.87 (m, 1H), 3.11-3.25 (m, 2H), 4.18-4.31 (m, 1H),4.39-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.54 (brs, 1H), 6.10(d, J=11.2 Hz, 1H), 6.37 (d, J=11.2 Hz, 1H). MS m/z: 298(M⁺—HS(CH₂)₃C(CH₃)₂OH), 91 (100%). UV λ_(max) nm: 263.

Example 43

[0386] (1)17-{4-triethylsilyloxy-4-methyl-(2Z)-pentenylthiomethyl}-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene

[0387]17-Acetylthiomethyl-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene(5 mg, 0.0133 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-(2Z)-pentene(10 mg, 0.0341 mmol), a 1M potassium hydroxide methanol solution (0.5ml) and tetrahydrofuran (0.5 ml) were subjected to reaction using aprocedure similar to that of Example 31(1) (at room temperature for 10min.) and worked up to give a mixture (5 mg) containing the titledcompound.

[0388] (2)1α,3β-dihydroxy-17-{4-hydroxy-4-methyl-(2Z)-pentenylthiomethyl}-9,10-secoandrosta-5,7,10(19),16-tetraene

[0389] The mixture (5 mg) obtained in the above (1), AMBERLYST 15 (1 g),methanol (2 ml) and tetrahydrofuran (2 ml) were subjected to reactionusing a procedure similar to that of Example 35(3) (at room temperaturefor 3 hours), worked up and purified by preparative thin layerchromatography (1 sheet (0.5 mm thickness), hexane:ethyl acetate=1:1,developed once; and 1 sheet (0.5 mm thickness),dichloromethane:ethanol=20:1, developed once) to give the titledcompound (1.54 mg, 27%) as a colorless foam. IR(neat): 3360, 2923, 2850,1437, 1363, 1142, 1055 cm⁻¹. ¹H NMR δ: 0.75 (s, 3H), 1.36 (s, 6H),2.75-2.86 (m, 1H), 3.22 (s, 2H), 3.39-3.58 (m, 2H), 4.18-4.29 (m, 1H),4.39-4.48 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.39-5.61 (m, 3H),6.10 (d, J=11.2 Hz, 1H), 6.37 (d, J=11.2 Hz, 1H). MS m/z: 412 (M⁺—H₂O),133 (100%). UV λ_(max) nm: 265.

Example 44

[0390] (1)17-{4-ethyl-4-triethylsilyloxy-(2Z)-hexenylthiomethyl}-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene

[0391]17-Acetylthiomethyl-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene(4 mg, 0.0107 mmol), 1-bromo-4-ethyl-4-triethylsilyloxy-(2Z)-hexene (10mg, 0.0311 mmol), a 1M potassium hydroxide methanol solution (0.5 ml)and tetrahydrofuran (0.5 ml) were subjected to reaction using aprocedure similar to that of Example 31(1) (10 min.) and worked up togive a mixture (4.0 mg) containing the titled compound.

[0392] (2)17-{4-ethyl-4-hydroxy-(2Z)-hexenylthiomethyl}-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraene

[0393] The mixture (4.0 mg) containing17-{4-ethyl-4-triethylsilyloxy-(2Z)-hexenylthiomethyl}-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraeneobtained in the above (1), a 1M tetra-n-butylammonium fluoridetetrahydrofuran solution (1.1 ml) and tetrahydrofuran (2 ml) weresubjected to reaction using a procedure similar to that of Example 5(2)(at room temperature for 3 days), worked up and purified by preparativethin layer chromatography (1 sheet (0.5 mm thickness), hexane:ethylacetate=1:1, developed once;. 1 sheet (0.5 mm thickness),dichloromethane:ethanol=10:1, developed once; 1 sheet (0.5 mmthickness), dichloromethane:acetonitrile=2:1, developed once; and 1sheet (0.5 mm thickness), toluene:ethyl acetate=1:1, developed twice) togive the titled compound (1.15 mg, 23%) as a colorless oil. IR(neat):3465, 2960, 2852, 1731, 1462, 1053 cm⁻¹. ¹H NMR δ: 0.75 (s, 3H), 0.91(t, J=7.3 Hz, 6H), 3.22 (s, 2H), 3.48 (d, J=8.3 Hz, 2H), 4.24 (brs, 1H),4.44 (brs, 1H), 5.01 (s, 1H), 5.30-5.66 (m, 4H), 6.10 (d, J=11.6 Hz,1H), 6.37 (d, J=11.6 Hz, 1H). MS m/z: 440 (M⁺−H₂O), 57 (100%). UVλ_(max) nm: 263.

Example 45

[0394] (1)1α,3β-bis(tert-butyldimethylsilyloxy)-17-methyleneandrost-5-ene

[0395] A mixture of tetrahydrofuran (70 ml), methyltriphenylphosphoniumbromide (50 g) and potassium t-butoxide (13.9 g) were stirred at 60° C.for 2 hours, while under suspension. To this suspension, was added1α,3β-bis(tert-butyldimethylsilyloxy)androst-5-ene (18.7 g) andtetrahydrofuran (60 ml), followed by reaction for 2 hours under reflux.Under cooling with ice, the reaction mixture was slowly added to acooled mixture of hexane (200 ml) and water (100 ml) to stop thereaction. The organic layer was washed with saturated brine twice, driedover anhydrous magnesium sulfate and evaporated under reduced pressureto remove the solvent, giving crude crystals (27 g). The crude crystalswere mixed with hexane (100 ml), stirred at room temperature while undersuspension. After filtering off insoluble material from the suspension,the filtrate was evaporated under reduced pressure to remove thesolvent, giving crude crystals, which were then dissolved in acetone (80ml) by stirring at room temperature. The mixture was mixed with methanol(160 ml) and stirred at room temperature; the thus precipitated crystalswere collected by filtration and dried to give the titled compound (13.2g). ¹H NMR δ: 5.4-5.5 (1H, m), 4.6-4.7 (2H, m), 3.9-4.1 (1H, m), 3.8(1H, br), 1.0-2.6 (17H, m), 0.99 (3H, s), 0.88 (9H, s), 0.87 (9H, s),0.80 (3H, s), 0.08 (3H, s), 0.06 (3H, s), 0.05 (3H, s), 0.03 (3H, s).

[0396] (2)1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(hydroxymethyl)androst-5-ene

[0397] To1α,3β-bis(tert-butyldimethylsilyloxy)-17-methyleneandrost-5-ene (30.3g), was added 9-borabicyclo[3,3,1]nonane (0.5M solution intetrahydrofuran, 228 ml) and reacted by stirring at room temperature for4 hours. Under cooling with ice, a 3M sodium hydroxide solution (150 ml)and then a 30% hydrogen peroxide solution (150 ml) were added to thereaction mixture, followed by stirring at room temperature for 1 hour.The reaction mixture was extracted with ethyl acetate, the organic layerwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure to remove the solvent, givingcrude crystals (37.3 g). The crude crystals were mixed with methanol,stirred while under suspension, filtered and the thus obtained crystalswere dried to give the titled compound (24.3 g). ¹H NMR δ: 5.4-5.5 (1H,m), 3.9-4.1 (1H, m), 3.8 (1H, br), 3.7 (1H, dd), 3.6 (1H, dd), 2.1-2.3(2H, m), 1.0-2.0 (17H, m), 0.97 (3H, s), 0.88 (9H, s), 0.81 (9H, s),0.66 (3H, s), 0.07 (3H, s), 0.05 (3H, s), 0.04 (3H, s), 0.02 (3H, s).

[0398] (3)1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(N,N-dimethylaminocarbonylethoxymethyl)androst-5-ene

[0399] To1α,3-bis(tert-butyldimethylsilyloxy)-17β-(hydroxymethyl)androst-5-ene(18.4 g), was added N,N-dimethylacrylamide (9.95 g), sodium hydride (60%in oil, 2.0 g), 15-crown-5 (2.2 g) and tetrahydrofuran (73.5 ml),followed by reaction at 0° C. for 8 hours. After stopping the reactionby adding a saturated aqueous ammonium chloride solution, the organiclayer was washed with a saturated aqueous sodium bicarbonate solutionand saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure to remove the solvent. The resultingresidue was mixed with methanol (90 ml), stirred at room temperaturewhile under suspension, followed by centrifugation. The thus obtainedsolid was dried to give the titled compound (13.2 g). ¹H NMR δ: 5.4-5.5(1H, m), 3.9-4.1 (1H, m), 3.8 (1H, br), 3.6-3.7 (2H, m), 3.4-3.5 (1H,dd), 3.3-3.4 (1H, dd), 3.0 (3H, s), 2.9 (3H, s), 2.5-2.6 (2H, m),2.1-2.4 (2H, m), 1.0-2.0 (16H, m), 0.95 (3H, s),0.86 (18H, s), 0.61 (3H,s), 0.05 (3H, s), 0.04 (3H, s), 0.03 (3H, s), 0.01 (3H, s).

[0400] (4)1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(N,N-dimethylaminocarbonylethoxymethyl)androsta-5,7-diene4-phenyl-1,2,4-triazoline-3,5-dione adduct

[0401] To1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(N,N-dimethylaminocarbonylethoxymethyl)androst-5-ene(15 g), were added N-bromosuccinimide (5.36 g), 2,2′-azobisisobutyronitrile (1.06 g), hexane (120 ml) and tetrahydrofuran (30 ml),followed by reflux under heating for 15 min. After cooling to roomtemperature, the mixture was filtered to remove insoluble material andthe filtrate was concentrated under reduced pressure. To the resultant,were added toluene (50 ml) and γ-collidine (9.8 ml), followed byreaction under reflux for 2 hours. After cooling to room temperature,the reaction mixture was filtered and the filtrate was washed with 0.5Mhydrochloric acid, a saturated aqueous sodium bicarbonate solution andthen saturated brine. The organic layer was dried over anhydrousmagnesium sulfate, concentrated under reduced pressure. To the thusobtained residue, were added dichloromethane (70 ml) and4-phenyl-1,2,4-triazoline-3,5-dione, followed by reaction at roomtemperature. The reaction mixture was washed with water, dried overanhydrous magnesium sulfate and evaporated under reduced pressure toremove the solvent. The thus obtained residue was purified by columnchromatography (hexane:ethyl acetate=1:2) to give the titled compound(7.43 g). ¹H NMR δ: 7.3-7.1 (5H, m), 6.2 (1H, d, J=8.2 Hz), 6.1 (1H, d,J=8.2 Hz), 4.6 (1H, m), 3.7 (1H, m), 3.6-3.5 (2H, m), 3.4-3.2 (1H, m),3.2-3.1 (1H, m), 2.9 (3H, s), 2.8 (3H, s), 0.8 (3H, s), 0.77 (9H, s),0.76 (9H, s), 0.64 (3H, s), 0.01 (3H, s), −0.02 (3H, s), −0.04 (3H, s),−0.06 (3H, s).

[0402] (5)1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(hydroxymethyl)androsta-5,7-diene4-phenyl-1,2,4-triazoline-3,5-dione adduct

[0403] To1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(N,N-dimethylaminocarbonylethoxymethyl)androsta-5,7-diene4-phenyl-1,2,4-triazoline-3,5-dione adduct (9 g), were addedtetrahydrofuran (90 ml) and then potassium t-butoxide (10.5 g), followedby reaction at room temperature for 10 min. After stopping the reactionby adding saturated brine, the reaction mixture was extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,evaporated under reduced pressure to remove the solvent and the thusobtained residue was purified by column chromatography (hexane:ethylacetate=2:1) to give the titled compound (6.34 g). ¹H NMR δ: 7.4-7.2(5H, m), 6.3 (1H, d, J=8.2 Hz), 6.2 (1H, d, J=8.2 Hz), 4.7 (1H, m), 3.8(1H, m), 3.7-3.6 (2H, m), 3.3-3.2 (1H, m), 0.90 (3H, s), 0.86 (9H, s),0.85 (9H, s), 0.77 (3H, s), 0.01 (3H, s), 0.07 (3H, s), 0.05 (3H, s),0.03 (3H, s).

[0404] (6)1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(hydroxymethyl)androsta-5,7-diene

[0405] To1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(hydroxymethyl)androsta-5,7-diene4-phenyl-1,2,4-triazoline-3,5-dione adduct (6.3 g), was added1,3-dimethyl-2-imidazolidinone (100 ml), followed by heating at 140° C.for 3 hours. The reaction mixture was extracted with hexane, the organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure to remove the solvent. Thethus obtained residue was purified by column chromatography(hexane:ethyl acetate=5:1) to give the titled compound (3.61 g). ¹H NMRδ: 5.6 (1H, m), 5.3 (1H, m), 4.0 (1H, m), 4.7 (1H, m), 4.0-3.7 (2H, m),3.6-3.7 (1H, m), 2.8 (1H, m), 2.4-2.3 (2H, m), 0.91 (3H, s), 0.88 (9H,s), 0.83 (9H, s), 0.61 (3H, s), 0.11 (3H, s), 0.06 (6H, s), 0.05 (3H,s).

[0406] (7) 1α,3β-dihydroxy-17β-(hydroxymethyl)androsta-5,7-diene

[0407] To1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(hydroxymethyl)androsta-5,7-diene(1.0 g), was added a 1M tetra-n-butylammonium fluoride tetrahydrofuransolution (11 ml), followed by reflux for 6 hours. After adding ethylacetate, the reaction mixture was washed with saturated brine, asaturated aqueous sodium bicarbonate solution (twice) and then saturatedbrine. The organic layer was dried over anhydrous magnesium sulfate,evaporated under reduced pressure to remove the solvent and the thusobtained residue was purified by column chromatography (hexane:ethylacetate=1:2) to give the titled compound (560 mg). ¹H NMR (DMSO-d6) δ:5.4 (1H, m), 5.3 (1H, m), 4.6 (1H, d, J=4.6 Hz), 4.4 (1H, d, J=4.6 Hz),4.2 (1H, m), 3.8 (1H, m), 3.5 (1H, br),3.6-3.4 (1H, m), 3.4-3.2 (1H, m),2.7-2.9 (1H, m), 0.9 (3H, s), 0.5 (3H, s). ¹³C NMR (DMSO-d6) δ: 140.4,138.7, 119.5, 114.7, 70.7, 63.2, 62.3, 53.7, 52.1, 41.7, 41.5, 40.4,38.6, 37.5, 37.1, 25.3, 23.0, 19.5, 15.8, 12.0.

[0408] (8)1α,3β-dihydroxy-17β-hydroxymethyl-9,10-secoandrosta-5,7,10(19)-triene

[0409] 1α,3β-Dihydroxy-17β-(hydroxymethyl)androsta-5,7-diene (200 mg)was dissolved in tetrahydrofuran (200 ml), subjected to irradiation for2 min. by 400 W high-pressure mercury lamp, refluxed for 1.5 hours andevaporated to remove the solvent under reduced pressure. The resultingresidue was mixed with acetone, stirred and then filtered to remove thethus formed precipitate. The filtrate was evaporated under reducedpressure to remove the solvent and the resulting residue was subjectedto high performance liquid chromatography (27% acetonitrile in water) togive the titled compound (16.33 mg). ¹H NMR δ: 6.4 (1H, d), 6.0 (1H, d),5.3 (1H, m), 5.0 (1H, m), 4.5-4.4 (1H, m), 4.3-4.2 (1H, m), 3.8-3.6 (1H,m), 3.6-3.5 (1H, m), 2.9-2.8 (1H, m), 2.6-2.5 (1H, m), 2.4-2.2 (1H, m),1.5 (3H, s), 0.5 (3H, s).

Example 46

[0410] (1)1α,3β-bis(tert-butyldimethylsilyloxy)-17β-{4-ethyl-4-(triethylsilyloxy)hexyloxymethyl}androst-5-ene

[0411]1α,3β-Bis(tert-butyldimethylsilyloxy)-17β-(hydroxymethyl)androst-5-ene(11.0 g) was dissolved in tetrahydrofuran. Under cooling with ice,potassium hydride (30% in oil, 200.3 g) and 18-crown-6 (2.64 g) wereadded to the solution, which was then stirred for 5 min.1-Bromo-4-ethyl-4-(triethylsilyloxy)hexane (25.91 g) was then added tothe mixture and reacted for 3.5 hours. After stopping the reaction byadding a saturated aqueous ammonium chloride solution, the mixture wasextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate, filtered and the filtrate was evaporated underreduced pressure to remove the solvent. The resulting residue waspurified by column chromatography (hexane:ethyl acetate=50:1) to givethe titled compound (15.8 g). ¹H NMR δ: 5.5 (1H, m), 4.0 (1H, m), 3.7(2H, m), 3.4-3.2 (4H, m), 2.4-2.1 (2H, m), 0.9-0.5 (10H, m), 0.07 (3H,s), 0.05 (3H, s), 0.04 (3H, s), 0.02 (3H, s).

[0412] (2)1α,3β-bis(tert-butyldimethylsilyloxy)-17β-{4-ethyl-4-(triethylsilyloxy)hexyloxymethyl}androsta-5,7-diene4-phenyl-1,2,4-triazoline-3,5-dione adduct

[0413] To1α,3β-bis(tert-butyldimethylsilyloxy)-17β-{4-ethyl-4-(triethylsilyloxy)hexyloxymethyl}androst-5-ene(1.0 g), were added hexane (15 ml), N-bromosuccinimide (336.4 mg) andthen 2,2′-azobis isobutyronitrile (77.6 mg), followed by reaction underreflux for 30 min. After cooling with ice, the mixture was filtered toremove insoluble material and the filtrate was evaporated under reducedpressure to remove the solvent. To the resulting residue, were addedtoluene (10 ml) and γ-collidine (534.4 mg), followed by reflux for 2hours. The mixture was filtered to remove insoluble material and thefiltrate was diluted with hexane. The organic layer was washed with IMhydrochloric acid, a saturated aqueous sodium bicarbonate solution andthen saturated brine and evaporated to remove the solvent under reducedpressure. The resulting residue was purified by column chromatography(hexane:ethyl acetate 40:1), dissolved in dichloromethane (20 ml) andsubjected to reaction for 1 hour by adding4-phenyl-1,2,4-triazoline-3,5-dione. The reaction mixture was evaporatedto remove the solvent under reduced pressure and the resulting residuewas purified by column chromatography (hexane:ethyl acetate=7:1) to givethe titled compound (0.45 g). ¹H NMR δ: 7.5-7.2 (5H, m), 6.3 (1H, d,J=8.2 Hz), 6.2 (1H, d, J=8.2 Hz), 4.7 (1H, m), 3.8 (1H, m), 3.5-3.2 (5H,m), 2.6-2.4 (3H, m), 0.6-0.5 (6H, m), 0.10 (3H, s), 0.07 (3H, s), 0.05(3H, s), 0.03 (3H, s).

[0414] (3)1α,3β-bis(tert-butyldimethylsilyloxy)-17β-{4-ethyl-4-(triethylsilyloxy)hexyloxymethyl}androsta-5,7-diene

[0415] After adding 1,3-dimethyl-2-imidazolidinone (10 ml) to1α,3β-bis(tert-butyldimethylsilyloxy)-17β-{4-ethyl-4-(triethylsilyloxy)hexyloxymethyl}androsta-5,7-diene4-phenyl-1,2,4-triazoline-3,5-dione adduct (0.45 g), the mixture washeated to 140° C. and reaction was proceeded for 2 hours. The reactionmixture was cooled and extracted with hexane. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure to remove the solvent. The resultingresidue was purified by column chromatography (hexane:ethylacetate=40:1) to give the titled compound (0.18 g). ¹H NMR δ: 5.6 (1H,m), 5.3 (1H, m), 4.0 (1H, m), 3.7 (1H, m), 3.5-3.3 (4H, m), 2.8 (1H, m),0.6-0.5 (9H, m), 0.07 (3H, s), 0.05 (3H, s), 0.04 (3H, s), 0.02 (3H, s).

[0416] (4)1α,3β-dihydroxy-17β-(4-ethyl-4-hydroxyhexyloxymethyl)androsta-5,7-diene

[0417] To1α,3=-bis(tert-butyldimethylsilyloxy)-17β-{4-ethyl-4-(triethylsilyloxy)hexyloxymethyl}androsta-5,7-diene(180 mg), was added a 1M tetra-n-butylammonium fluoride tetrahydrofuransolution (6 ml), followed by reflux under heating for 5 hours. Afteradding ethyl acetate, the mixture was washed with saturated brine, asaturated aqueous sodium bicarbonate solution and then saturated brine.The organic layer was dried over anhydrous magnesium sulfate, evaporatedunder reduced pressure to remove the solvent and the resulting residuewas purified by column chromatography (ethyl acetate) to give the titledcompound (0.10 g). ¹H NMR δ: 5.7 (1H, m), 5.3 (1H, m), 4.0 (1H, m), 3.7(1H, m), 3.6-3.2 (6H, m), 0.6 (3H, s). ¹³C NMR δ: 140.3, 138.7, 119.5,114.8, 72.2, 71.7, 71.0, 70.7, 63.2, 53.5, 49.2, 41.9, 41.5, 40.4, 38.6,37.5, 37.0, 34.2, 30.6, 25.2, 23.6, 23.1, 19.5, 15.9, 12.0, 7.7.

[0418] (5)1α,3β-dihydroxy-17β-(4-ethyl-4-hydroxyhexyloxymethyl)-9,10-secoandrosta-5,7,10(19)-triene

[0419]1α,3β-Dihydroxy-17β-(4-ethyl-4-hydroxyhexyloxymethyl)androsta-5,7-diene(204 mg) was dissolved in tetrahydrofuran (200 ml), subjected toirradiation by 400 W high-pressure mercury lamp for 2.5 min., refluxedfor 2.5 hours and evaporated to remove the solvent under reducedpressure. The resulting residue was subjected to high performance liquidchromatography (methanol:acetonitrile:water=4:3:3) to give the titledcompound (11.0 mg). ¹H NMR δ: 6.4 (1H, d, J=10.8 Hz), 6.1 (1H, d, J=10.8Hz), 5.3 (1H, m), 5.0 (1H, m), 4.4 (1H, m), 4.2 (1H, m), 3.4-3.2 (5H,m), 2.9 (1H, m), 2.6 (1H, m), 2.3 (1H, m), 1.0-0.8 (6H, m), 0.5 (3H, s).¹³C NMR δ: 147.6, 142.8, 133.0, 124.9, 117.1, 111.8, 73.9, 72.8, 71.8,70.9, 66.9, 55.8, 50.3, 45.3, 45.1, 42.9, 39.1, 35.5, 31.0, 30.9, 29.1,25.3, 23.9, 23.3, 22.6, 12.5, 7.9.

Example 47

[0420] (1)1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(3-hydroxy-3-methylbutoxymethyl)androsta-5,7-diene

[0421] To1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(N,N-dimethylaminocarbonylethoxymethyl)androsta-5,7-diene4-phenyl-1,2,4-triazoline-3,5-dione adduct (2.3 g), was added1,3-dimethyl-2-imidazolidinone (30 ml), followed by heating at 140° C.for 3 hours. The reaction mixture was extracted with hexane, the organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure to remove the solvent. Theresulting residue was purified by column chromatography (hexane:ethylacetate=1:2) to give1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(N,N-dimethylaminocarbonylethoxymethyl)androsta-5,7-diene.To a suspension of anhydrous cerous (III) chloride (2.6 g) andtetrahydrofuran (8.3 ml), was added a 1.0M methylmagnesiumbromide/tetrahydrofuran solution (8.7 ml) at 0° C., followed by stirringfor 0.5 hours. The reaction mixture and the above-obtained1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(N,N-dimethylaminocarbonylethoxymethyl)androsta-5,7-diene(1.5 g) were mixed and reacted for 1 hour. The reaction mixture wasadded to a mixture of potassium hydrogen sulfate solution and hexanecooled at −10° C. in order to stop the reaction and then filtered. Theorganic layer was dried over anhydrous magnesium sulfate, evaporatedunder reduced pressure to remove the solvent and the resultant wasreacted for 1 hour with Grignard solution, which was prepared as above.The thus obtained reaction mixture was worked up as above and purifiedby column chromatography (hexane:ethyl acetate=7:1) to give the titledcompound (730 mg). ¹H NMR δ: 5.6 (1H, m), 5.3 (1H, m), 4.0 (1H, m),3.8-3.6 (3H, m), 3.5 (1H, m), 3.3 (1H, m), 3.2 (1H, br), 2.8 (1H, m),2.3 (2H, m), 0.91 (3H, s), 0.91 (9H, s), 0.90 (9H, s), 0.58 (3H, s),0.10 (3H, s), 0.06 (3H, s), 0.05 (3H, s).

[0422] (2)1α,3β-dihydroxy-17β-(3-hydroxy-3-methylbutoxymethyl)androsta-5,7-diene

[0423] To1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(3-hydroxy-3-methylbutoxymethyl)androsta-5,7-diene(700 mg), was added a 1M tetra-n-butylammonium fluoride tetrahydrofuransolution (20 ml), followed by reaction for 6 hours. After adding ethylacetate, the reaction mixture was washed with saturated brine, asaturated aqueous sodium bicarbonate solution and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, evaporatedunder reduced pressure to remove the solvent and the resulting residuewas purified by column chromatography (dichloromethane: methanol=9:1) togive the titled compound (0.41 g). ¹H NMR (DMSO-d6) δ: 5.5 (1H, m), 5.3(1H, m), 4.6 (1H, d, J=4.6 Hz), 4.4 (1H, d, J=4.6 Hz), 4.1 (1H, m),3.5-3.3 (3H, m), 3.2 (1H, m), 2.8 (1H, m), 2.3 (1H, m), 2.1 (1H, m), 1.1(6H, s), 0.8 (3H, s), 0.5 (3H, s). ¹³C NMR (DMSO-d6) δ: 140.2, 138.8,119.5, 114.8, 71.9, 70.7, 68.1, 67.3, 63.2, 53.5, 49.2, 42.7, 41.8,41.5, 40.3, 38.9, 37.4, 37.0, 29.7, 29.6, 25.3, 23.0, 19.5, 15.8, 12.0.

[0424] (3)1α,3β-dihydroxy-17β-(3-hydroxy-3-methylbutoxymethyl)-9,10-secoandrosta-5,7,10(19)-triene

[0425]1α,3β-Dihydroxy-17β-(3-hydroxy-3-methylbutoxymethyl)androsta-5,7-diene(150 mg) was dissolved in tetrahydrofuran (200 ml), subjected toirradiation for 2 min. by 400 W high-pressure mercury lamp, refluxed for2.5 hours and then evaporated to remove the solvent under reducedpressure. The resulting residue was subjected to high performance liquidchromatography (methanol:acetonitrile:water=3.5:2.5:4) to give thetitled compound (33.0 mg). ¹H NMR δ: 6.4 (1H, d, J=10.8 Hz), 6.1 (1H, d,J=10.8 Hz), 5.3 (1H, m), 5.0 (1H, m), 4.4 (1H, m), 4.2 (1H, m), 3.8-3.5(4H, m), 3.3 (1H, m), 2.8 (1H, m), 2.6 (1H, m), 2.3 (1H, m), 1.5 (6H,s), 1.2 (3H, s), 0.5 (3H, s). ¹³C NMR δ: 147.6, 142.6, 133.0, 124.9,117.2, 111.8, 73.3, 70.9, 70.6, 68.8, 66.8, 55.8, 50.4, 45.3, 45.0,42.9, 41.3, 39.0, 29.5, 29.0, 25.2, 23.3, 22.6, 12.6.

Example 48

[0426] (1)1α,3β-bis(tert-butyldimethylsilyloxy)-17-methylandrosta-5,7,17-triene

[0427] A suspension of1α,3β-bis(tert-butyldimethylsilyloxy)-17-oxoandrosta-5,7-diene (723 mg,1.36 mmol), methyltriphenylphosphonium bromide (632 mg, 1.77 mmol) andpotassium tert-butoxide (198 mg, 1.77 mmol) in tetrahydrofuran (5 ml)was subjected to reflux under heating for 1 hour. The reaction mixturewas returned to room temperature, mixed with hexane (20 ml) and filteredto remove insoluble material. The filtrate was washed with water twice,dried over anhydrous magnesium sulfate and evaporated under reducedpressure to remove the solvent. The thus obtained residue was purifiedby column chromatography (hexane:dichloromethane=9:1) to give the titledcompound (599 mg, 83%) as a colorless oil. IR(neat): 2954, 2929, 2887,2856, 1462, 1371, 1254, 1097, 1082 cm⁻¹. ¹H NMR δ: 0.06 (s, 3H), 0.07(s, 6H), 0.11 (s, 3H), 0.74 (s, 3H), 0.88 (s, 9H), 0.89 (s, 9H), 0.93(s, 3H), 2.46-2.65 (m, 1H), 2.7 5-2.89 (m, 1H), 3.70-3.75 (m, 1H),3.98-4.13 (m, 1H), 4.65-4.75 (m, 2H), 5.35-5.43 (m, 1H), 5.56-5.64 (m,1H).

[0428] (2)1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(hydroxymethyl)androsta-5,7-diene

[0429] To a solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17-methylandrosta-5,7,17-triene(593 mg, 1.12 mmol) in tetrahydrofuran (4 ml), was added dimer of9-borabicyclo[3,3,1]nonane (273 mg, 1.12 mmol), followed by stirring atexternal temperature of 45° C. for 2 hours. After cooling the reactionmixture in an ice bath, a 3M aqueous sodium hydroxide solution (4 ml)and then 30% hydrogen peroxide solution (3 ml) were added dropwise,followed by stirring at room temperature for 2 hours. The reactionmixture was poured into water and extracted with ethyl acetate. Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure to remove thesolvent. The thus obtained residue was purified by column chromatography(hexane:ethyl acetate=7:1) to give the titled compound (465 mg, 76%) asa white solid. The thus obtained compound had the same spectra as thoseof the compound obtained in Example 45(6).

[0430] (3)1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(methanesulfonyloxymethyl)androsta-5,7-diene

[0431] A solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(hydroxymethyl)androsta-5,7-diene(150 mg, 0.274 mmol) and triethylamine (0.153 ml, 1.10 mmol) intetrahydrofuran (2.3 ml) was cooled to 0° C., followed by the additionof methanesulfonyl chloride (63 μl, 0.814 mmol) and stirring at 0° C.for 1 hour. The reaction mixture was diluted with hexane, washed withwater and saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure to remove the solvent. The thusobtained residue was purified by column chromatography (hexane:ethylacetate=9:1) to give the titled compound (155 mg, 91%) as a colorlessfoam. IR(neat): 2954, 2929, 2897, 2856, 1471, 1360, 1176, 1097, 1066cm¹. ¹H NMR δ: 0.05 (s, 3H), 0.06 (s, 6H), 0.11 (s, 3H), 0.64 (s, 3H),0.88 (s, 18H), 0.91 (s, 3H), 3.00 (s, 3H), 3.67-3.74 (m, 1H), 3.97-4.12(m, 1H), 4.13-4.22 (m, 1H), 4.23-4.32 (m, 1H), 5.29-5.37 (m, 1H),5.55-5.62 (m, 1H). UV λ_(max) nm: 271, 282, 294.

[0432] (4)1α,3β0-bis(tert-butyldimethylsilyloxy)-17β-(acetylthiomethyl)androsta-5,7-diene

[0433] A mixture of1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(methanesulfonyloxymethyl)androsta-5,7-diene(155 mg, 0.248 mmol), potassium thioacetate (56.6 mg, 0.496 mmol) and18-crown-6 (65.6 mg, 0.248 mmol) in tetrahydrofuran (4 ml) was subjectedto reflux under heating for 20 hours. The reaction mixture was returnedto room temperature. After adding a saturated aqueous ammonium chloride,the reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with water and saturated brine, driedover magnesium sulfate and evaporated under reduced pressure to removethe solvent. The thus obtained residue was purified by columnchromatography (hexane:dichloromethane=3:12:1) to give the titledcompound (135 mg, 90%) as a yellow oil. IR(neat): 2954, 2929, 2897,2856, 1693, 1471, 1360, 1254, 1099 cm⁻¹. ¹H NMR δ: 0.05 (s, 3H), 0.06(s, 6H), 0.11 (s, 3H), 0.60 (s, 3H), 0.878 (s, 9H), 0.882 (s, 9H), 0.91(s, 3H), 2.32 (s, 3H), 2,74 (dd, J=12.9, 9.7 Hz, 1H), 3.04 (dd, J=12.9,5.3 Hz, 1H), 3.67-3.75 (m, 1H), 3.97-4.12 (m, 1H), 5.27-5.34 (m, 1H),5.54-5.61 (m, 1H). MS m/z: 604 (M⁺), 415 (100%). UV λ_(max) nm: 271,282, 294.

[0434] (5)1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(3-hydroxy-3-methylbutylthiomethyl)androsta-5,7-diene

[0435] To a solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(acetylthiomethyl)androsta-5,7-diene(135 mg, 0.223 mmol) and 4-bromo-2-methylbutan-2-ol (186 mg, 1.12 mmol)in tetrahydrofuran (1.5 ml), was added a 1M potassium hydroxide methanolsolution (1.5 ml), followed by stirring at room temperature for 1 hour.The reaction mixture was concentrated under reduced pressure, followedby the addition of a saturated aqueous ammonium chloride solution andthe extraction with ethyl acetate. The extract was washed with water andsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure to remove the solvent. The thus obtained residuewas purified by preparative thin layer chromatography (4 sheets (each0.5 mm thickness), dichloromethane:ethyl acetate=9:1, developed once) togive the titled compound (131 mg, 90%) as a colorless oil. IR(neat):3388, 2954, 2929, 2897, 2856, 1462, 1377, 1254, 1099, 1082 cm⁻¹. ¹H NMRδ: 0.05 (s, 3H), 0.06 (s, 6H), 0.11 (s, 3H), 0.58 (s, 3H), 0.88 (s,18H), 0.91 (s, 3H), 1.23 (s, 6H), 2.71 (dd, J=11.8, 5.1 Hz, 1H),2.75-2.87 (m, 1H), 3.67-3.74 (m, 1H), 3.96-4.12 (m, 1H), 5.28-5.35 (m,1H), 5.54-5.61 (m, 1H). MS m/z: 648 (M⁺), 459 (100%). UV λ_(max) nm:271, 282, 294.

[0436] (6)1α,3β-dihydroxy-17β-(3-hydroxy-3-methylbutylthiomethyl)androsta-5,7-diene

[0437] To a solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(3-hydroxy-3-methylbutylthiomethyl)androsta-5,7-diene(130 mg, 0.215 mmol) in tetrahydrofuran (1 ml), was added a 1Mtetra-n-butylammonium fluoride tetrahydrofuran solution (2.15 ml, 2.15mmol), followed by reflux under heating for 5 hours. The reactionmixture was returned to room temperature, diluted with ethyl acetate,washed with water and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure to remove the solvent. Thethus obtained residue was purified by preparative thin layerchromatography (3 sheets (each 0.5 mm thickness),dichloromethane:ethanol=9:1, developed once) to give the titled compound(75.9 mg, 84%) as a white solid. ¹H NMR (CD₃OD) δ: 0.66 (s, 3H), 0.97(s, 3H), 1.24 (s, 6H), 2.75 (dd, J=12.1, 5.2 Hz, 1H), 2.81-2.94 (m, 1H),3.73-3.80 (m, 1H), 3.92-4.10 (m, 1H), 5.35-5.34 (m, 1H), 5.62-5.71 (m,1H). MS m/z: 420 (M⁺), 119 (100%). UV λ_(max) nm: 272, 282, 294.

[0438] (7)1α,3β-dihydroxy-17β-(3-hydroxy-3-methylbutylthiomethyl)-9,10-secoandrosta-5,7,10(19)-triene

[0439]1α,3β-Dihydroxy-17β-(3-hydroxy-3-methylbutylthiomethyl)androsta-5,7-diene(60.5 mg, 0.144 mmol) was dissolved in ethanol (200 ml). While stirringthe solution and bubbling argon thereinto at 0° C., the solution wasirradiated by a 400 W high-pressure mercury lamp with a Vycor filter for6.5 min. and then refluxed under heating for 2 hours. The reactionmixture was cooled to room temperature, evaporated under reducedpressure to remove the solvent and the thus obtained residue waspurified by preparative thin layer chromatography (2 sheets (each 0.5 mmthickness), dichloromethane:ethanol=9:1, developed once; and 1 sheet(0.25 mm thickness), dichloromethane:ethyl acetate:ethanol 7:3:0.5,developed three times) to give the titled compound (7.36 mg, 12%) as acolorless oil. IR(neat): 3367, 2927, 2871, 2843, 1435, 1377, 1209, 1147,1055 cm⁻¹. ¹H NMR δ: 0.51 (s, 3H), 1.24 (s, 6H), 2.70 (dd, J=11.9, 4.9Hz, 1H), 2.80-2.90 (m, 1H), 4.17-4.28 (m, 1H), 4.38-4.47 (m, 1H), 4.99(brs, 1H), 5.32 (m, 1H), 6.01 (d, J=11.3 Hz, 1H), 6.37 (d, J=11.3 Hz,1H). MS m/z: 420 (M⁺), 134 (100%). UV λ_(max) nm: 262.

Test Example 1

[0440] Active vitamin D₃ (1α,25 (OH)₂vitamin D₃) dissolved in ethanol atthe concentration of 125 μg/ ml, Compounds 1 to 13 (the vitamin Dderivatives obtained in the above Examples) dissolved in ethanol at theconcentration of 500 μg/ml and ethanol alone (as control) werepercutaneously applied once to the dorsal skin of respective 8-week-oldmale Balb/c mice (approximately 1.5×2.0 cm²). The dosage was 2 ml/kg andeach mouse received a necklace to prevent ingestion. On the next day,the application areas were cleaned and necklaces were removed from themice. Two days after the application, blood was drawn from each mouse inorder to measure the ionized calcium level in the blood by an ionselective electrode method. In this experiment, each group contained 3mice. Results are shown in Table 18. The ionized calcium levels in theTable indicate the mean values.

Test Example 2

[0441] Keratinocytes derived from human neonatal foreskin (Clonetics)were inoculated in 96 well-plates (COSTAR 3595) at 2×10³ cells/well.Active vitamin D₃ (1α,25(OH)₂D₃) and Compounds 1 to 13 at variousconcentrations were added to respective wells and cultured at 2×10³cells/200 μl/well in KGM-2 medium for 3 days at 37° C. in 5% CO₂ and 95%air. After adding [³H] thymidine at 7.4 kBq/well, the cell culture wascontinued for further 1 day. After washing the wells with phosphatebuffer free of calcium and magnesium (Dulbecco PBS(−), NISSUI, code05913, pH 7.3 to 7.65) once, the cells were stripped using 0.25%tyrosine. The [³H] thymidine uptake of the cells was measured by aliquid scintillation counter (1450 microbeta, WALLAC). Results are shownin Table 18. In the Table, the inhibition of human keratinocyteproliferation is expressed as follows: the relative value of eachCompound with respect to active vitamin D₃=[IC₅₀ (mol/l) of1α,25(OH)₂vitamin D₃]/[IC₅₀ (mol/l) of each Compound] TABLE 18 Humankeratinocyte Ionized Ca proliferation Dosage level inhibition (μg/kg)(mmol/l) (relative value) Control — 1.34 — 1α, 25(OH)₂D₃  250 2.66 1.0Compound 1 1000 1.52 0.6 Compound 2 1000 2.12 1.9 Compound 3 1000 1.811.2 Compound 4 1000 1.68 0.7 Compound 5 1000 1.63 1.8 Compound 6 10002.32 4.1 Compound 7 1000 1.85 1.5 Compound 8 1000 1.93 1.7 Compound 91000 2.33 2.1 Compound 10 1000 2.38 1.7 Compound 11 1000 2.38 23.0Compound 12 1000 2.34 2.7 Compound 13 1000 2.38 10.7

[0442] Compound 1 is1α,3β-dihydroxy-17-(3-hydroxy-3-methylbutoxymethyl)-9,10-secoandrosta-5,7,10(19),16-tetraeneobtained in Example 23(4), Compound 2 is17-(4-ethyl-4-hydroxyhexyloxymethyl)-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraeneobtained in Example 6(3), Compound 3 is1α,3β-dihydroxy-17-(5-hydroxy-5-methylhexyloxymethyl)-9,10-secoandrosta-5,7,10(19),16-tetraeneobtained in Example 7(3), Compound 4 is1α,3β-dihydroxy-17-(4-hydroxy-4-methylpentyloxymethyl)-9,10-secoandrosta-5,7,10(19),16-tetraeneobtained in Example 5(3), Compound 5 is1α,3β-dihydroxy-17-(4-hydroxy-4-methyl-2-pentynyloxymethyl)-9,10-secoandrosta-5,7,10(19),16-tetraeneobtained in Example 8(3), Compound 6 is17-{4-ethyl-4-hydroxy-(2E)-hexenyloxymethyl}-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraeneobtained in Example 10(3), Compound 7 is17-(4-ethyl-4-hydroxy-2-hexynyloxymethyl)-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraeneobtained in Example 11(3), Compound 8 is1α,3β-dihydroxy-17-(4-hydroxy-4-methyl-2-pentynylthiomethyl)-9,10-secoandrosta-5,7,10(19),16-tetraeneobtained in Example 39, Compound 9 is1α,3β-dihydroxy-17-(3-ethyl-3-hydroxypentyloxymethyl)-9,10-secoandrosta-5,7,10(19),16-tetraeneobtained in Example 25(4), Compound 10 is17-(4-ethyl-4-hydroxy-2-hexynylthiomethyl)-1α,3β-dihydroxy-9,10-secoandrosta-5,7,10(19),16-tetraeneobtained in Example 40, Compound 11 is1α,3β-dihydroxy-20-(4-hydroxy-4-methyl-2-pentynyloxy)-20-methyl-9,10-secopregna-5,7,10(19),16-tetraeneobtained in Example 15(3), Compound 12 is1α,3β-dihydroxy-20-(5-hydroxy-5-methylhexyloxy)-20-methyl-9,10-secopregna-5,7,10(19),16-tetraeneobtained in Example 14 and Compound 13 is1α,3β-dihydroxy-20-(4-ethyl-4-hydroxy-2-hexynyloxy)-20-methyl-9,10-secopregna-5,7,10(19),16-tetraeneobtained in Example 18(3).

INDUSTRIAL APPLICABILITY

[0443] Vitamin D derivatives of the present invention exhibit excellentphysiological activity and have reduced hypercalcemic effect as comparedwith conventional vitamin D derivatives; they may be useful as medicinesfor diseases, to which the administration of vitamin D derivatives hasbeen restricted because of hypercalcemia, etc.

1. A vitamin D derivative of Formula (1):

wherein in Formula (1), X is oxygen or sulfur; R₁ is hydrogen or Formula(2)

wherein in Formula (2), A is —CO—, —CR₉R₁₀— in which R₉ and R₁₀ arehydrogen or hydroxy, —CR₁₁=CR₁₂— in which R₁₁ and R₁₂ are hydrogen oralkyl or —C≡C—; R₇ and R₈ are hydrogen or hydroxy which may have aprotecting group; m is a number from 0 to 4; and n is a number from 0 to2; R₂ is hydrogen or alkyl; R₃ and R₄ are hydrogen or alkyl or R₃ and R₄together form a double bond between the 16- and 17-positions; R₅ ishydrogen or —OR₁₃ in which R₁₃ is hydrogen or a protecting group; and R₆is hydrogen or a protecting group.
 2. The vitamin D derivative as setforth in claim 1, wherein in Formula (1), X is oxygen or sulfur; R₁ ishydrogen or Formula (2) wherein A is —CO—, —CH₂—, —CH(OH)—, —CH═CH— or—C≡C—, R₇ is hydroxy, R₈ is hydrogen, m is a number from 0 to 2 and n isa number from 0 to 1; R₂ is hydrogen or C₁₋₄ alkyl; R₃ and R₄ ishydrogen or R₃ and R₄ together form a double bond between the 16- and17-positions; R₅ is hydroxy; and R₆ is hydrogen.
 3. The vitamin Dderivative as set forth in claim 1, wherein in Formula (1), X is oxygenor sulfur; R₁ is Formula (2) wherein A is —CO—, —CH₂—, —CH(OH)—, —CH═CH—or C≡C—, R₇ is hydroxy, R₈ is hydrogen, m is a number from 0 to 2 and nis a number from 0 to 1; R₂ is hydrogen or methyl; R₃ and R₄ togetherform a double bond between the 16- and 17-positions; R₅ is hydroxy; andR₆ is hydrogen.
 4. The vitamin D derivative as set forth in claim 1,wherein in Formula (1), X is oxygen or sulfur; R₁ is Formula (2) whereinA is —CO—, —CH₂—, —CH═CH— or —C≡C—, R₇ is hydroxy, R₈ is hydrogen, m isa number from 0 to 1 and n is a number from 0 to 1; R₂ is hydrogen ormethyl, R₃ and R₄ together form a double bond between the 16- and17-positions; R₅ is hydroxy; and R₆ is hydrogen.
 5. The vitamin Dderivative as set forth in claim 1, wherein in Formula (1), X is oxygen;R₁ is Formula (2) wherein A is —CH₂— or —C≡C—, R₇ is hydroxy, R₈ ishydrogen, m is 1 and n is a number from 0 to 1; R₂ is hydrogen ormethyl; R₃ and R₄ together form a double bond between the 16- and17-positions; R₅ is hydroxy; and R₆ is hydrogen.
 6. The vitamin Dderivative as set forth in claim 1, wherein in Formula (1), X is oxygen;R₁ is Formula (2) wherein A is —C≡C—, R₇ is hydroxy, R₈ is hydrogen, mis 1 and n is 0; R₂ is hydrogen or methyl; R₃ and R₄ together form adouble bond between the 16- and 17-positions; R₅ is hydroxy; and R₆ ishydrogen.
 7. The vitamin D derivative as set forth in claim 1, whereinin Formula (1), X is oxygen; R₁ is hydrogen or Formula (2) wherein A is—CH₂—, R₇ is hydroxy, R₈ is hydrogen, m is a number from 1 to 2 and n isa number from 0 to 1; R₂ is hydrogen; R₃ and R₄ are hydrogen; R₅ ishydroxy; and R₆ is hydrogen.
 8. A pharmaceutical composition comprisingthe vitamin D derivative as set forth in any one of claims 1 to
 7. 9. Atherapeutic agent for skin disease comprising the vitamin D derivativeas set forth in any one of claims 1 to 7 as an active ingredient. 10.The therapeutic agent as set forth in claim 9, wherein the skin diseaseis psoriasis.